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Introduction: Coronary artery disease (CAD) is the foremost single cause of mortality and disability globally. Patients with type 2 diabetes (T2DM) have a higher incidence of CAD, and poorer prognosis. The low-grade inflammation associated to T2DM contributes to increased morbidity and worst outcomes after revascularization. Inflammatory signaling in the vasculature supports endothelial dysfunction, leukocyte infiltration, and macrophage activation to a metabolic disease (MMe) specific phenotype, which could contribute to the metabolic disorders and ascular damage in T2DM. We have previously found that Kv1.3 blockers inhibit the development of intimal hyperplasia, thereby preventing restenosis. This inhibition was enhanced in a mouse model of T2DM, where systemic Kv1.3 blockers administration also improve metabolic dysfunction by acting on unidentified cellular targets other than vascular smooth muscle. Here we characterize the MMe phenotype in our T2DM model with a focus on macrophage Kv1.3 channels, to explore their contribution to vascular disease and their potential role as targets to ameliorate T2DM vascular risk. Methods and Results: Male and female BPH mice fed on high-fat diet (HFD) develop metabolic syndrome (MetS) and T2DM. mRNA levels of several K+ channels (KV1.3, KCa3.1, Kir2.1) and macrophage markers (TNFα, NOS2, CD36) were analyzed. The MMe phenotype associated with increased CD36 expression. Channel-specific fingerprinting highlights a gender-specific increase of KV1.3 mRNA fold change in LPS stimulated macrophages from HFD compared to standard diet (SD). KV1.3 functional expression was also significantly increased after LPS stimulation in female HFD macrophages compared to SD. Functional studies showed that macrophage's KV1.3 channels of BPH female mice did not contribute to phagocytosis or metabolic profile but were relevant in cell migration rate. Conclusion: Altogether, our data suggest that by inhibiting macrophage infiltration, Kv1.3 blockers could contribute to disrupt the vicious cycle of inflammation and insulin resistance, offering a novel approach to prevent MetS, T2DM and its associated cardiovascular complications in females. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin‐1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus‐W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered. In this study, C57BL/6 mice were injected with adeno‐associated virus‐overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real‐time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin‐eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial‐ and motor neurons‐related proteins. Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule‐associated protein 2, HB9, neuronal nuclei and neuron‐specific enolase in Syn‐induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration. This study provides evidence that Syn‐activated microglia plays a pivotal role during the progression of ALS. [ABSTRACT FROM AUTHOR]

IntroductionCoronary artery disease (CAD) is the foremost single cause of mortality and disability globally. Patients with type 2 diabetes (T2DM) have a higher incidence of CAD, and poorer prognosis. The low-grade inflammation associated to T2DM contributes to increased morbidity and worst outcomes after revascularization. Inflammatory signaling in the vasculature supports endothelial dysfunction, leukocyte infiltration, and macrophage activation to a metabolic disease (MMe) specific phenotype, which could contribute to the metabolic disorders and ascular damage in T2DM. We have previously found that Kv1.3 blockers inhibit the development of intimal hyperplasia, thereby preventing restenosis. This inhibition was enhanced in a mouse model of T2DM, where systemic Kv1.3 blockers administration also improve metabolic dysfunction by acting on unidentified cellular targets other than vascular smooth muscle. Here we characterize the MMe phenotype in our T2DM model with a focus on macrophage Kv1.3 channels, to explore their contribution to vascular disease and their potential role as targets to ameliorate T2DM vascular risk.Methods and ResultsMale and female BPH mice fed on high-fat diet (HFD) develop metabolic syndrome (MetS) and T2DM. mRNA levels of several K+ channels (KV1.3, KCa3.1, Kir2.1) and macrophage markers (TNFα, NOS2, CD36) were analyzed. The MMe phenotype associated with increased CD36 expression. Channel-specific fingerprinting highlights a gender-specific increase of KV1.3 mRNA fold change in LPS stimulated macrophages from HFD compared to standard diet (SD). KV1.3 functional expression was also significantly increased after LPS stimulation in female HFD macrophages compared to SD. Functional studies showed that macrophage's KV1.3 channels of BPH female mice did not contribute to phagocytosis or metabolic profile but were relevant in cell migration rate.ConclusionAltogether, our data suggest that by inhibiting macrophage infiltration, Kv1.3 blockers could contribute to disrupt the vicious cycle of inflammation and insulin resistance, offering a novel approach to prevent MetS, T2DM and its associated cardiovascular complications in females.

Abstract Background Biomaterials used in bone tissue engineering must fulfill the requirements of osteoconduction, osteoinduction, and osseointegration. However, biomaterials with good osteoconductive properties face several challenges, including inadequate vascularization, limited osteoinduction and barrier ability, as well as the potential to trigger immune and inflammatory responses. Therefore, there is an urgent need to develop guided bone regeneration membranes as a crucial component of tissue engineering strategies for repairing bone defects. Methods The mZIF-8/PLA membrane was prepared using electrospinning technology and simulated body fluid external mineralization method. Its ability to induce biomimetic mineralization was evaluated through TEM, EDS, XRD, FT-IR, zeta potential, and wettability techniques. The biocompatibility, osteoinduction properties, and osteo-immunomodulatory effects of the mZIF-8/PLA membrane were comprehensively evaluated by examining cell behaviors of surface-seeded BMSCs and macrophages, as well as the regulation of cellular genes and protein levels using PCR and WB. In vivo, the mZIF-8/PLA membrane’s potential to promote bone regeneration and angiogenesis was assessed through Micro-CT and immunohistochemical staining. Results The mineralized deposition enhances hydrophilicity and cell compatibility of mZIF-8/PLA membrane. mZIF-8/PLA membrane promotes up-regulation of osteogenesis and angiogenesis related factors in BMSCs. Moreover, it induces the polarization of macrophages towards the M2 phenotype and modulates the local immune microenvironment. After 4-weeks of implantation, the mZIF-8/PLA membrane successfully bridges critical bone defects and almost completely repairs the defect area after 12-weeks, while significantly improving the strength and vascularization of new bone. Conclusions The mZIF-8/PLA membrane with dual osteoconductive and immunomodulatory abilities could pave new research paths for bone tissue engineering.

Background: Biomaterials used in bone tissue engineering must fulfill the requirements of osteoconduction, osteoinduction, and osseointegration. However, biomaterials with good osteoconductive properties face several challenges, including inadequate vascularization, limited osteoinduction and barrier ability, as well as the potential to trigger immune and inflammatory responses. Therefore, there is an urgent need to develop guided bone regeneration membranes as a crucial component of tissue engineering strategies for repairing bone defects. Methods: The mZIF-8/PLA membrane was prepared using electrospinning technology and simulated body fluid external mineralization method. Its ability to induce biomimetic mineralization was evaluated through TEM, EDS, XRD, FT-IR, zeta potential, and wettability techniques. The biocompatibility, osteoinduction properties, and osteo-immunomodulatory effects of the mZIF-8/PLA membrane were comprehensively evaluated by examining cell behaviors of surface-seeded BMSCs and macrophages, as well as the regulation of cellular genes and protein levels using PCR and WB. In vivo, the mZIF-8/PLA membrane's potential to promote bone regeneration and angiogenesis was assessed through Micro-CT and immunohistochemical staining. Results: The mineralized deposition enhances hydrophilicity and cell compatibility of mZIF-8/PLA membrane. mZIF-8/PLA membrane promotes up-regulation of osteogenesis and angiogenesis related factors in BMSCs. Moreover, it induces the polarization of macrophages towards the M2 phenotype and modulates the local immune microenvironment. After 4-weeks of implantation, the mZIF-8/PLA membrane successfully bridges critical bone defects and almost completely repairs the defect area after 12-weeks, while significantly improving the strength and vascularization of new bone. Conclusions: The mZIF-8/PLA membrane with dual osteoconductive and immunomodulatory abilities could pave new research paths for bone tissue engineering. [ABSTRACT FROM AUTHOR]

Wound healing involves distinct phases, including hemostasis, inflammation, proliferation, and remodeling, which is a complex and dynamic process. Conventional preparations often fail to meet multiple demands and provide prompt information about wound status. Here, a pH/ROS dual-responsive hydrogel (OHA-PP@ Z -CA@EGF) was constructed based on oxidized hyaluronic acid (OHA), phenylboronic acid-grafted ε-polylysine (PP), chlorogenic acid (CA)-loaded ZIF-8 (Z-CA), and epidermal growth factor (EGF), which possesses intrinsic antibacterial, antioxidant, and angiogenic capacities. Due to the Schiff base and Phenylboronate ester bonds, the hydrogel exhibited excellent mechanical properties, strong adhesion, good biodegradability, high biocompatibility, stable rheological properties, and self-healing ability. Moreover, introducing Z -CA as an initiator and nanofiller led to the additional cross-linking of hydrogel through coordination bonds, which further improved the mechanical properties and antioxidant capabilities. Bleeding models of liver and tail amputations demonstrated rapid hemostatic properties of the hydrogel. Besides, the hydrogel regulated macrophage phenotypes via the NF-κB/JAK-STAT pathways, relieved oxidative stress, promoted cell migration and angiogenesis, and accelerated diabetic wound healing. The hydrogel also enabled real-time monitoring of the wound healing stages by colorimetric detection. This multifunctional hydrogel opens new avenues for the treatment and management of full-thickness diabetic wounds. [Display omitted] • A pH/ROS responsive nanocomposite hydrogel was constructed with antibacterial and antioxidant capacity. • The tri-cross-linked hydrogel was composed of Schiff base, Phenylboronate ester, and coordination bonds. • The hydrogel regulated macrophage phenotypes via the NF-κB/JAK-STAT pathways. • The hydrogel enabled real-time visual and accelerated diabetic wounds healing. [ABSTRACT FROM AUTHOR]

Introduction: The last decade has led to rapid developments and increased usage of computational tools at the single-cell level. However, our knowledge remains limited in how extracellular cues alter quantitative macrophage morphology and how such morphological changes can be used to predict macrophage phenotype as well as cytokine content at the single-cell level. Methods: Using an artificial intelligence (AI) based approach, this study determined whether (i) accurate macrophage classification and (ii) prediction of intracellular IL-10 at the single-cell level was possible, using only morphological features as predictors for AI. Using a quantitative panel of shape descriptors, our study assessed image-based original and synthetic single-cell data in two different datasets in which CD14+ monocyte-derived macrophages generated from human peripheral blood monocytes were initially primed with GM-CSF or M-CSF followed by polarization with specific stimuli in the presence/ absence of continuous GM-CSF or M-CSF. Specifically, M0, M1 (GM-CSF-M1, TNFα/IFNγ-M1, GM-CSF/TNFα/IFNγ-M1) and M2 (M-CSF-M2, IL-4-M2a, M-CSF/ IL-4-M2a, IL-10-M2c, M-CSF/IL-10-M2c) macrophages were examined. Results: Phenotypes were confirmed by ELISA and immunostaining of CD markers. Variations of polarization techniques significantly changed multiple macrophage morphological features, demonstrating that macrophage morphology is a highly sensitive, dynamic marker of phenotype. Using original and synthetic single-cell data, cell morphology alone yielded an accuracy of 93% for the classification of 6 different human macrophage phenotypes (with continuous GM-CSF or M-CSF). A similarly high phenotype classification accuracy of 95% was reached with data generated with different stimuli (discontinuous GM-CSF or M-CSF) and measured at a different time point. These comparably high accuracies clearly validated the here chosen AI-based approach. Quantitative morphology also allowed prediction of intracellular IL-10 with 95% accuracy using only original data. Discussion: Thus, image-based machine learning using morphology-based features not only (i) classified M0, M1 and M2 macrophages but also (ii) classified M2a and M2c subtypes and (iii) predicted intracellular IL-10 at the single-cell level among six phenotypes. This simple approach can be used as a general strategy not only for macrophage phenotyping but also for prediction of IL-10 content of any IL-10 producing cell, which can help improve our understanding of cytokine biology at the single-cell level. [ABSTRACT FROM AUTHOR]

Canine hemangiosarcoma (HSA) is a highly malignant tumor derived from hematopoietic stem cells and commonly occurs in visceral organs or skin. Visceral HSAs are particularly aggressive and progress rapidly despite multimodal treatment. Tumor-associated macrophages (TAMs) play a central role in carcinogenesis, tumor progression, and metastasis in humans and murine models. In this retrospective study, we investigated the prevalence and phenotype of TAMs in privately owned, treatment-naïve dogs with naturally occurring HSA. We used CD204 as a general macrophage marker and CD206 as a marker for M2-polarized macrophages. Formalin-fixed paraffin-embedded tissues from HSAs in the spleen (n = 9), heart (n = 6), and other locations (n = 12) from 17 dogs were sectioned and immunohistochemically labeled with CD204 and CD206 antibodies. The mean number of log(CD204)- and log(CD206)-positive cells and the ratio of log(CD206/CD204)-positive cells were compared with normal surrounding tissues and between tumor locations. There were significantly more macrophages and M2 macrophages, and a higher ratio of M2 macrophages to total macrophages in tumor hot spots (P =.0002, P <.0001, and P =.0002, respectively) and in tumor tissues outside of hot spots (P =.009, P =.002, and P =.007, respectively) than in normal surrounding tissues. There were no significant differences between tumor locations, but there was a trend toward higher numbers of CD204-positive macrophages within the splenic tumors. There was no association between histological parameters or clinical stage and TAM numbers or phenotype. As in humans, TAMs in dogs with HSA have a predominantly M2-skewed phenotype. Dogs with HSA could serve as excellent models to evaluate new TAM-reprogramming therapies. [ABSTRACT FROM AUTHOR]

IntroductionThe last decade has led to rapid developments and increased usage of computational tools at the single-cell level. However, our knowledge remains limited in how extracellular cues alter quantitative macrophage morphology and how such morphological changes can be used to predict macrophage phenotype as well as cytokine content at the single-cell level.MethodsUsing an artificial intelligence (AI) based approach, this study determined whether (i) accurate macrophage classification and (ii) prediction of intracellular IL-10 at the single-cell level was possible, using only morphological features as predictors for AI. Using a quantitative panel of shape descriptors, our study assessed image-based original and synthetic single-cell data in two different datasets in which CD14+ monocyte-derived macrophages generated from human peripheral blood monocytes were initially primed with GM-CSF or M-CSF followed by polarization with specific stimuli in the presence/absence of continuous GM-CSF or M-CSF. Specifically, M0, M1 (GM-CSF-M1, TNFα/IFNγ-M1, GM-CSF/TNFα/IFNγ-M1) and M2 (M-CSF-M2, IL-4-M2a, M-CSF/IL-4-M2a, IL-10-M2c, M-CSF/IL-10-M2c) macrophages were examined.ResultsPhenotypes were confirmed by ELISA and immunostaining of CD markers. Variations of polarization techniques significantly changed multiple macrophage morphological features, demonstrating that macrophage morphology is a highly sensitive, dynamic marker of phenotype. Using original and synthetic single-cell data, cell morphology alone yielded an accuracy of 93% for the classification of 6 different human macrophage phenotypes (with continuous GM-CSF or M-CSF). A similarly high phenotype classification accuracy of 95% was reached with data generated with different stimuli (discontinuous GM-CSF or M-CSF) and measured at a different time point. These comparably high accuracies clearly validated the here chosen AI-based approach. Quantitative morphology also allowed prediction of intracellular IL-10 with 95% accuracy using only original data.DiscussionThus, image-based machine learning using morphology-based features not only (i) classified M0, M1 and M2 macrophages but also (ii) classified M2a and M2c subtypes and (iii) predicted intracellular IL-10 at the single-cell level among six phenotypes. This simple approach can be used as a general strategy not only for macrophage phenotyping but also for prediction of IL-10 content of any IL-10 producing cell, which can help improve our understanding of cytokine biology at the single-cell level.

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The innate immune system is the first line of defense against external threats through the initiation and regulation of inflammation. Macrophage differentiation into functional phenotypes influences the fate of nanomaterials taken up by these immune cells. High-resolution electron microscopy was used to investigate the uptake, distribution, and biotransformation of nanoceria in human and murine M1 and M2 macrophages in unprecedented detail. We found that M1 and M2 macrophages internalize nanoceria differently. M1-type macrophages predominantly sequester nanoceria near the plasma membrane, whereas nanoceria are more uniformly distributed throughout M2 macrophage cytoplasm. In contrast, both macrophage phenotypes show identical nanoceria biotransformation to cerium phosphate nanoneedles and simultaneous nanoceria with ferritin co-precipitation within the cells. Ferritin biomineralization is a direct response to nanoparticle uptake inside both macrophage phenotypes. We also found that the same ferritin biomineralization mechanism occurs after the uptake of Ce-ions into polarized macrophages and into unpolarized human monocytes and murine RAW 264.7 cells. These findings emphasize the need for evaluating ferritin biomineralization in studies that involve the internalization of nano objects, ranging from particles to viruses to biomolecules, to gain greater mechanistic insights into the overall immune responses to nano objects. [ABSTRACT FROM AUTHOR]

Chronic widespread pain (CWP) is associated with a high rate of disability and decreased quality of life in people with HIV-1 (PWH). We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs β-endorphin synthesis/release from leukocytes. However, the cellular mechanisms by which heme dampens β-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-α, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low β-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl/6 mice increased the M1/M2 cell ratio and reduced β-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1/M2 ratio and increased β-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV. [ABSTRACT FROM AUTHOR]

Introduction. Macrophages are phenotypically heterogeneous cells that play a vital role in hepatic fibrogenesis. We aimed to compare the macrophage profiles between normal livers and those with various chronic liver diseases in the precirrhotic fibrosis stage. Methods. Immunohistochemistry was performed for three macrophage markers (CD163, CD68, and IBA1) on 48 liver biopsies. Digital image analysis and automated cell count were used to calculate the densities of immunostained cells in two selected regions of interest: the periportal region and the perivenous region. Results. The absolute and relative densities of the macrophage phenotypes in relationship with zones and etiologies showed four distinct patterns by hierarchical cluster analysis: (1) no significant increase in the macrophage densities in either periportal or perivenous regions - nonalcoholic steatohepatitis; (2) significant increase in the selected macrophage densities in both periportal and perivenous regions - Hepatitis C; (3) significant increase in the macrophage densities only in periportal region - alcoholic liver disease, primary sclerosing cholangitis, and primary biliary cholangitis; and (4) significant increase in the densities of all types of macrophages in both periportal and perivenous regions - autoimmune hepatitis. Conclusions. There are distinct macrophage phenotypic and zonal geographic signatures correlating to etiologies of chronic liver disease in the precirrhotic stage. [ABSTRACT FROM AUTHOR]

Pro-inflammatory and anti-inflammatory types are the main phenotypes of the macrophage, which are commonly notified as M1 and M2, respectively. The alteration of macrophage phenotypes and the progression of inflammation are intimately associated; both phenotypes usually coexist throughout the whole inflammation stage, involving the transduction of intracellular signals and the secretion of extracellular cytokines. This paper aims to address the interaction of macrophages and surrounding cells and tissues with inflammation-related diseases and clarify the crosstalk of signal pathways relevant to the phenotypic metamorphosis of macrophages. On these bases, some novel therapeutic methods are proposed for regulating inflammation through monitoring the transition of macrophage phenotypes so as to prevent the negative effects of antibiotic drugs utilized in the long term in the clinic. This information will be quite beneficial for the diagnosis and treatment of inflammation-related diseases like pneumonia and other disorders involving macrophages. [ABSTRACT FROM AUTHOR]

Background Macrophage polarization and microRNA play crucial roles in the development of atherosclerosis (AS). The M1 macrophage phenotype contributes to the formation of plaques, while the M2 macrophage phenotype resolves inflammation and promotes tissue repair. MiR-126 has been found to play a role in regulating macrophage polarization in the context of AS. However, the exact mechanism of miR-126 requires further research. Methods The foam cell model was established by stimulating THP-1 with oxidized low-density lipoprotein (ox-LDL). We transfected foam cells with miR-126 mimic and its negative control. The transfection of miR-126 was implemented by riboFECT CP transfection kit. The levels of miR-126 and M1/M2 associated genes in foam cells were quantified using reverse transcription-quantitative PCR (RT-qPCR). Additionally, the expressions of CD86+ and CD206+ cells in foam cells were determined by flow cytometry. Western blotting and RT-qPCR were used to determine the protein and mRNA levels of the vascular endothelial growth factor A (VEGFA) and the transcriptional regulator Krüppel-like factor 4 (KLF4), respectively. Additionally, we detected endothelial cell migration after co-culturing endothelial cells and macrophages. MG-132 was used to indirectly activate the expression of VEGFA, and the expression of KLF4 was also evaluated. Results The activation of apoptosis and production of foam cells were boosted by the addition of ox-LDL. We transfected foam cells with miR-126 mimic and its negative control and observed that miR-126 greatly suppressed foam cell development and inhibited phagocytosis. Moreover, it caused pro-inflammatory M1 macrophages to switch to the anti-inflammatory M2 phenotype. This was reflected by the increase in anti-inflammatory gene expression and the decrease in pro-inflammatory gene expression. Additionally, miR-126 dramatically decreased the expressions of VEGFA and KLF4. The protein-protein interaction network analysis showed a significantly high correlation between miR-126, VEGFA, and KLF4. MiR-126 may also promote EC migration by activating macrophage PPAR γ expression and effectively suppressing macrophage inflammation. MG-132 indirectly activated the expression of VEGFA, and the expression of KLF4 also significantly increased, which indicates a direct or indirect relationship between VEGFA and KLF4. Conclusion Our study shows that miR-126 can reverse ox-LDL-mediated phagocytosis and apoptosis in macrophages. Consequently, the potential role of miR-126 was manifested in regulating macrophage function and promoting vascular endothelial migration. [ABSTRACT FROM AUTHOR]

Duchenne Muscular Dystrophy (DMD) is a very severe X-linked dystrophinopathy. It is due to a mutation in the DMD gene and causes muscular degeneration in conjunction with several secondary co-morbidities, such cardiomyopathy and respiratory failure. DMD is characterized by a chronic inflammatory state, and corticosteroids represent the main therapy for these patients. To contradict drug-related side effects, there is need for novel and more safe therapeutic strategies. Macrophages are immune cells stringently involved in both physiological and pathological inflammatory processes. They express the CB2 receptor, one of the main elements of the endocannabinoid system, and have been proposed as an anti-inflammatory target in several inflammatory and immune diseases. We observed a lower expression of the CB2 receptor in DMD-associated macrophages, hypothesizing its involvement in the pathogenesis of this pathology. Therefore, we analyzed the effect of JWH-133, a CB2 receptor selective agonist, on DMD-associated primary macrophages. Our study describes the beneficial effect of JWH-133 in counteracting inflammation by inhibiting pro-inflammatory cytokines release and by directing macrophages' phenotype toward the M2 anti-inflammatory one. [ABSTRACT FROM AUTHOR]

Timely and appropriate transformation of macrophage phenotypes from proinflammatory to anti-inflammatory is essential for cardiac repair after myocardial infarction (MI). Chemokine-like receptor 1 (CMKLR1), which is expressed on macrophages, is regulated by proinflammatory and anti-inflammatory stimuli. However, the contribution of CMKLR1 to macrophage phenotypic transformation and the role it plays in modulating cardiac repair after MI remain unclear. CMKLR1 knockout (CMKLR1−/−) mice were generated by CRISPR/Cas-mediated genome engineering. A model of murine MI was induced by permanent ligation along the left anterior descending artery. Cardiac function was evaluated by echocardiography. Infarct size and collagen deposition were detected by Masson's trichrome staining. Cardiac macrophages were obtained by fluorescence-activated cell sorting. The protein and mRNA expression of associated molecules was determined by Western blotting and qRT–PCR. We demonstrated that macrophages highly expressed CMKLR1 and accumulated in murine infarcted hearts during the anti-inflammatory reparative phase of MI. CMKLR1 deficiency impaired cardiac function, increased infarct size, induced maladaptive cardiac remodeling, and decreased long-term survival after MI. Furthermore, CMKLR1 deficiency impeded macrophage phenotypic transformation from M1 to M2 in vivo and in vitro. In addition, we demonstrated that CMKLR1 signaling through the PI3K/Akt/mTOR pathway stimulated C/EBPβ activation while simultaneously limiting NF-κB activation, thereby promoting anti-inflammatory and prohibiting proinflammatory macrophage polarization. Our results reveal that CMKLR1 deficiency impedes macrophage phenotypic transformation and cardiac repair after MI involving the PI3K/AKT/mTOR pathway. CMKLR1 may thus represent a potential therapeutic target for MI. [Display omitted] • CMKLR1-expressing macrophages accumulate in murine infarcted hearts after MI. • CMKLR1 deficiency impedes cardiac repair after MI. • CMKLR1 deficiency impedes macrophage phenotypic transformation after MI. • CMKLR1 deficiency impedes macrophage phenotype transformation in BMDMs. • The PI3K/Akt/mTOR pathway is involved in CMKLR1-mediated macrophage polarization. [ABSTRACT FROM AUTHOR]

Macrophages are important cells of the innate immune system that play many different roles in host defense, a fact that is reflected by their polarization into many distinct subtypes. Depending on their function and phenotype, macrophages can be grossly classified into classically activated macrophages (pro-inflammatory M1 cells), alternatively activated macrophages (anti-inflammatory M2 cells), and non-activated cells (resting M0 cells). A fast, label-free and non-destructive characterization of macrophage phenotypes could be of importance for studying the contribution of the various subtypes to numerous pathologies. In this work, single cell Raman spectroscopic imaging was applied to visualize the characteristic phenotype as well as to discriminate between different human macrophage phenotypes without any label and in a non-destructive manner. Macrophages were derived by differentiation of peripheral blood monocytes of human healthy donors and differently treated to yield M0, M1 and M2 phenotypes, as confirmed by marker analysis using flow cytometry and fluorescence imaging. Raman images of chemically fixed cells of those three macrophage phenotypes were processed using chemometric methods of unmixing (N-FINDR) and discrimination (PCA-LDA). The discrimination models were validated using leave-one donor-out cross-validation. The results show that Raman imaging is able to discriminate between pro- and anti-inflammatory macrophage phenotypes with high accuracy in a non-invasive, non-destructive and label-free manner. The spectral differences observed can be explained by the biochemical characteristics of the different phenotypes. [ABSTRACT FROM AUTHOR]

• Using MCC950 to inhibit NLRP3 activation is able to promote diabetic wound healing in the DFU mouse model. • The administration of MCC950 promotes M2 macrophage polarization and enables the expansion of MDSCs in the DFU model. • Depleting MDSCs attenuated the therapeutic effects of MCC950. • BMDM co-cultured with MCC950-treated MDSCs has the potential of M2 phenotype polarization. Diabetic foot ulcers (DFUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Currently, there is a lack of effective therapeutic strategies. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has been reported to show strong anti-inflammation effects in many diseases. In this study, we unveiled the role of MCC950 in DFU mice model and its underlying molecular mechanisms. MCC950 could significantly accelerate diabetic wound healing, as shown by shortened healing time and better healing quality. Moreover, increased M2 phenotype macrophages and decreased pro-inflammatory genes were observed in MCC950-treated DFU mice. Additionally, myeloid-derived suppressor cells (MDSCs) were significantly increased in blood, spleen and wound tissues at different time courses. Specifically, MCC950 could recruit more MDSCs in an early phase in DFU mice, exerting an anti-inflammation effect. We identified the cell crosstalk between macrophages and MDSCs with MCC950 treatment process. Depleting MDSCs in vivo could eliminate the therapeutic effect of MCC950 on diabetic wound healing through inhibiting M2 macrophage polarization. Besides, MDSCs isolated from the wounds of MCC950 or saline treated mice were cocultured with bone marrow derived macrophage (BMDM) in a transwell system. Results confirmed that MDSCs sorted from MCC950 treated mice caused a significant increased percentage of M2 macrophages. Collectively, our findings suggest that the administration of MCC950 has the potential to accelerate diabetic wound healing by promoting M2 macrophage polarization in an MDSC-dependent manner. This study provides valuable insights into the utilization of pharmacological agents for DFU treatment. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the leading cause of death worldwide, with myocardial infarction (MI) being the primary contributor to mortality and disability associated with CVD. Reperfusion therapies are widely recognized as effective strategies for treating MI. However, while intended to restore blood flow, the reperfusion processes paradoxically initiate a series of pathophysiological events that worsen myocardial injury, resulting in ischemia-reperfusion (I/R) injury. Therefore, there is a pressing need for new treatment strategies to reduce the size of MI and enhance cardiac function post-infarction. Macrophages are crucial for maintaining homeostasis and mitigating undesirable remodeling following MI. Extensive research has established a strong link between cellular metabolism and macrophage function. In the context of MI, macrophages undergo adaptive metabolic reprogramming to mount an immune response. Moreover, mitochondrial metabolism in macrophages is evident, leading to significant changes in their metabolism. Therefore, we need to delve deeper into summarizing and understanding the relationship and role between mitochondrial metabolism and macrophage phenotype, and summarize existing treatment methods. In this review, we explore the role of mitochondria in shaping the macrophage phenotype and function. Additionally, we summarize current therapeutic strategies aimed at modulating mitochondrial metabolism of macrophages, which may offer new insights treating of MI. [Display omitted] • The importance of understanding the mitochondrial dysfunction within macrophages and their impact on cardiac repair and inflammation post-MI has been underscored. • We emphasize the plasticity of macrophage phenotype in the heart and their critical role in maintaining cardiac homeostasis. • We identify therapeutic strategies modulating macrophage mitochondrial metabolism as a potential approach to improve cardiac function after MI. [ABSTRACT FROM AUTHOR]

Innate immunity, particularly macrophages, is critical for intestinal homeostasis. Sulforaphane, a dietary isothiocyanate from cruciferous vegetables, has been reported to protect against intestinal inflammation. However, the role of macrophages in sulforaphane mediated intestinal inflammation and the underlying molecular mechanisms have not been studied yet. In this study, sulforaphane effectively attenuated dextran sodium sulphate (DSS) induced intestinal inflammation in murine model. Of note, sulforaphane skewed the switching from classically (M1) to alternatively (M2) activated phenotype both in intestinal and bone marrow-derived macrophages (BMDMs). The expression levels of M1 associated maker genes induced by DSS or lipopolysaccharide (LPS) plus interferon gamma-γ (IFN-γ) were suppressed by sulforaphane while M2 marker gene expression levels were improved. This resulted in alteration of inflammatory mediators, particularly interleukin-10 (IL-10), both in colon tissues and culture medium of BMDMs. Subsequently, IL-10 was found to mediate the sulforaphane induced M2 phenotype switching of BMDMs through the activation of STAT3 signaling. This was confirmed by immunofluorescence analysis with increased number of p-STAT3-positive cells in the colon sections. Moreover, anti-IL-10 neutralizing antibody significantly interfered M2 phenotyping of BMDMs induced by sulforaphane with reduced STAT3 phosphorylation. Findings here introduced a potential utilization of sulforaphane for intestinal inflammation treatment with macrophages as the therapeutic targets.

Background: Incisional hernia is a common complication following laparotomy. Obesity increases the incidence of incisional hernia by about three-fold. However, the pathophysiology behind the formation of incisional hernia is not well described. Methods: The current literature was reviewed, investigating the effect of the pro-inflammatory state of adipose tissue in obesity on post-operative wound healing and subsequent incisional hernia formation. Results: The increase in leptin, M1 macrophages, and pro-inflammatory cytokines and concomitant decrease in adiponectin, M2 macrophages, and anti-inflammatory cytokines seen with the hypertrophy of adipocytes in obesity creates a chronic inflammatory state that impacts wound healing. Prolonged inflammation disrupts the interaction of endothelial tip cells and formation of vessel lumens during angiogenesis and decreases ratio of type I to type III collagen and number of cross-links, resulting in decreased tensile strength of the ECM and association with incisional hernia formation. Conclusion: Obesity has impacts on the inflammatory, fibroproliferative, and wound remodeling stages of wound healing that are suggested to contribute to incisional hernia formation. Further studies are needed to investigate the pathophysiology of incisional hernia formation in the setting of obesity to decrease the incidence of incisional hernias and identify possible treatments.

Moderate‐intensity exercise performed during wound healing has been reported to decrease inflammatory cytokines and chemokines and accelerate wound healing. However, its effect on macrophage phenotype and the mechanism by which exercise accelerates wound healing remain unclear. The purpose of this study was to investigate the effect of exercise on macrophage phenotype during wound healing and to clarify the relationship between angiogenesis and wound healing. 12‐week‐old male C57BL/6J mice were divided into sedentary (n = 6) and exercise groups (n = 6). The exercise group performed moderate‐intensity treadmill running exercise (9.0 m/min, 60 min) for 10 days. Double immunofluorescence analysis was performed using F4/80+ inducible nitric oxide synthase (iNOS)+ for M1 macrophages, F4/80+ transforming growth factor‐beta (TGF‐β)1+ for M2 macrophages, and CD31+ alpha smooth muscle actin (α‐SMA)+ for angiogenesis. The exercise group showed significantly accelerated wound healing compared with the sedentary group. From early wound healing onward, exercise significantly inhibited M1 macrophage infiltration and increased M2 macrophage count. Exercise also significantly increased angiogenesis. Furthermore, the M2 macrophage phenotype was significantly correlated with angiogenesis in the exercise group, indicating that M2 macrophages and angiogenesis are related to accelerated wound healing. These findings suggest that moderate‐intensity exercise increases TGF‐β1 derived from M2 macrophages, which may be associated with enhanced angiogenesis and wound healing in young mice. [ABSTRACT FROM AUTHOR]

Due to the critical roles of macrophage in immune response and tissue repair, harnessing macrophage phenotypes dynamically to match the tissue healing process on demand attracted many attentions. Although there have developed many advanced platforms with dynamic features for cell manipulation, few studies have designed a dynamic chemical pattern to sequentially polarize macrophage phenotypes and meet the immune requirements at various tissue repair stages. Here, we propose a novel strategy for spatiotemporal manipulation of macrophage phenotypes by a UV-induced dynamic Arg-Gly-Asp (RGD) pattern. By employing a photo-patterning technique and the specific interaction between cyclodextrin (CD) and azobenzene-RGD (Azo-RGD), we prepared a polyethylene glycol-dithiol/polyethylene glycol-norbornene (PEG-SH/PEG-Nor) hydrogel with dynamic RGD-patterned surface. After irradiation with 365-nm UV light, the homogeneous RGD surface was transformed to the RGD-patterned surface which induced morphological transformation of macrophages from round to elongated and subsequent phenotypic transition from pro-inflammation to anti-inflammation. The mechanism of phenotypic polarization induced by RGD pattern was proved to be related to Rho-associated protein kinase 2 (ROCK2). Sequential modulation of macrophage phenotypes by the dynamic RGD-patterned surface provides a remote and non-invasive strategy to manipulate immune reactions and achieve optimized healing outcomes.

Abstract Moderate‐intensity exercise performed during wound healing has been reported to decrease inflammatory cytokines and chemokines and accelerate wound healing. However, its effect on macrophage phenotype and the mechanism by which exercise accelerates wound healing remain unclear. The purpose of this study was to investigate the effect of exercise on macrophage phenotype during wound healing and to clarify the relationship between angiogenesis and wound healing. 12‐week‐old male C57BL/6J mice were divided into sedentary (n = 6) and exercise groups (n = 6). The exercise group performed moderate‐intensity treadmill running exercise (9.0 m/min, 60 min) for 10 days. Double immunofluorescence analysis was performed using F4/80+ inducible nitric oxide synthase (iNOS)+ for M1 macrophages, F4/80+ transforming growth factor‐beta (TGF‐β)1+ for M2 macrophages, and CD31+ alpha smooth muscle actin (α‐SMA)+ for angiogenesis. The exercise group showed significantly accelerated wound healing compared with the sedentary group. From early wound healing onward, exercise significantly inhibited M1 macrophage infiltration and increased M2 macrophage count. Exercise also significantly increased angiogenesis. Furthermore, the M2 macrophage phenotype was significantly correlated with angiogenesis in the exercise group, indicating that M2 macrophages and angiogenesis are related to accelerated wound healing. These findings suggest that moderate‐intensity exercise increases TGF‐β1 derived from M2 macrophages, which may be associated with enhanced angiogenesis and wound healing in young mice.

The innate immune system is the first line of defense against external threats through the initiation and regulation of inflammation. Macrophage differentiation into functional phenotypes influences the fate of nanomaterials taken up by these immune cells. High-resolution electron microscopy was used to investigate the uptake, distribution, and biotransformation of nanoceria in human and murine M1 and M2 macrophages in unprecedented detail. We found that M1 and M2 macrophages internalize nanoceria differently. M1-type macrophages predominantly sequester nanoceria near the plasma membrane, whereas nanoceria are more uniformly distributed throughout M2 macrophage cytoplasm. In contrast, both macrophage phenotypes show identical nanoceria biotransformation to cerium phosphate nanoneedles and simultaneous nanoceria with ferritin co-precipitation within the cells. Ferritin biomineralization is a direct response to nanoparticle uptake inside both macrophage phenotypes. We also found that the same ferritin biomineralization mechanism occurs after the uptake of Ce-ions into polarized macrophages and into unpolarized human monocytes and murine RAW 264.7 cells. These findings emphasize the need for evaluating ferritin biomineralization in studies that involve the internalization of nano objects, ranging from particles to viruses to biomolecules, to gain greater mechanistic insights into the overall immune responses to nano objects.

Marketed dosage forms fail to deliver anti-tubercular drugs directly to the lungs in pulmonary Tuberculosis (TB). Therefore, nanomediated isoniazid (INH)-loaded dry powder for inhalation (Nano-DPI) was developed for macrophage-targeted delivery in TB. Mannosylated chitosan (MC) and hyaluronic acid (HA) with an affinity for the surface mannose and CD44 receptors of macrophages were used in conjugation to prepare hybrid nanosuspension by ionic gelation method using cross-linker, sodium tri-polyphosphate (TPP) followed by freeze-drying to obtain a dry powder composed of nanoparticles (INH-MC/HA NPs). Nanoformulations were evaluated for aerodynamic characteristics, cytotoxicity, hemocompatibility, macrophage phenotype analysis, and immune regulation. Cellular uptake imaging was also conducted to evaluate the uptake of NPs. The nanopowders did not pose any significant toxicity to the cells, along with good compatibility with red blood cells (RBCs). The pro-inflammatory costimulatory markers were upregulated, demonstrating the activation of T-cell response. Moreover, the NPs did not show any tolerogenic effect on the macrophages. Furthermore, confocal imaging exhibited the translocation of NPs in the cells. Altogether, the findings present that nano-DPI was found to be a promising vehicle for targeting macrophages. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is characterized by chronic skeletal muscle necrosis, leading to muscle regeneration failure and fibrosis. Although macrophages (MPs) are normally essential for muscle regeneration, dysregulated MP function promotes pathological muscle remodelling. Infiltrating MPs can be predominantly pro-inflammatory (M1 biased), anti-inflammatory (M2 biased) or of a mixed phenotype and can originate from the adult bone marrow (monocyte dependent) or embryonic precursors (monocyte independent). In mdx mice (genetic model of DMD) lacking either Toll-like receptor (Tlr) 2 or Tlr4, it is found that MP infiltration of dystrophic muscle is significantly reduced and that the MP phenotype is shifted toward a more anti-inflammatory profile. This is accompanied by significant improvements in muscle histology and force production. Lack of the chemokine receptor CCR2, which impedes monocyte release from the bone marrow, leads to similar beneficial effects in mdx mice. Evidence was also found for Tlr4-regulated induction of trained innate immunity in MPs cultured from the bone marrow of mdx mice before their entry into the muscle. These MPs exhibit epigenetic and metabolic alterations, accompanied by non-specific hyper-responsiveness to multiple stimuli, which is manifested by potentiated upregulation of both pro- and anti-inflammatory genes. In summary, exaggerated recruitment of monocyte-derived MPs and signs of trained innate immunity at the level of the bone marrow are features of the immunophenotype associated with dystrophic muscle disease. These phenomena are regulated by Toll-like receptors that bind endogenous damage-associated molecular pattern (DAMP) molecules, suggesting that DAMP release from dystrophic muscles modulates MP plasticity at the bone marrow level through Toll-like receptor-driven mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Background Sex and age are emerging as influential variables that affect spinal cord injury (SCI) recovery. Despite a changing demographic towards older age at the time of SCI, the effects of sex or age on inflammation remain to be elucidated. This study determined the sex- and age-dependency of the innate immune response acutely after SCI. Methods Male and female mice of ages 4- and 14-month-old received T9 contusion SCI and the proportion of microglia, monocyte-derived macrophages (MDM), and neutrophils surrounding the lesion were determined at 3- and 7-day post-injury (DPI) using flow cytometry. Cell counts of microglia and MDMs were obtained using immunohistochemistry to verify flow cytometry results at 3-DPI. Microglia and MDMs were separately isolated using fluorescence-activated cell sorting (FACS) at 3-day post-injury (DPI) to assess RNA expression of 27 genes associated with activation, redox, and debris metabolism/clearance. Results Flow cytometry revealed that being female and older at the time of injury significantly increased MDMs relative to other phagocytes, specifically increasing the ratio of MDMs to microglia at 3-DPI. Cell counts using immunohistochemistry revealed that male mice have more total microglia within SCI lesions that can account for a lower MDM/microglia ratio. With NanoString analyses of 27 genes, only 1 was differentially expressed between sexes in MDMs; specifically, complement protein C1qa was increased in males. No genes were affected by age in MDMs. Only 2 genes were differentially regulated in microglia between sexes after controlling for false discovery rate, specifically CYBB (NOX2) as a reactive oxygen species (ROS)-associated marker as well as MRC1 (CD206), a gene associated with reparative phenotypes. Both genes were increased in female microglia. No microglial genes were differentially regulated between ages. Differences between microglia and MDMs were found in 26 of 27 genes analyzed, all expressed higher in MDMs with three exceptions. Specifically, C1qa, cPLA2, and CD86 were expressed higher in microglia. Conclusions These findings indicate that inflammatory responses to SCI are sex-dependent at both the level of cellular recruitment and gene expression.

Chronic widespread pain (CWP) is associated with a high rate of disability and decreased quality of life in people with HIV-1 (PWH). We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs β-endorphin synthesis/release from leukocytes. However, the cellular mechanisms by which heme dampens β-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-α, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low β-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl/6 mice increased the M1/M2 cell ratio and reduced β-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1/M2 ratio and increased β-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV.

Leishmaniasis is a complex infectious parasitic disease caused by protozoa of the genus Leishmania, belonging to a group of neglected tropical diseases. It establishes significant global health challenges, particularly in socio-economically disadvantaged regions. Macrophages, as innate immune cells, play a crucial role in initiating the inflammatory response against the pathogens responsible for this disease. Macrophage polarization, the process of differentiating macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, is essential for the immune response in leishmaniasis. The M1 phenotype is associated with resistance to Leishmania infection, while the M2 phenotype is predominant in susceptible environments. Notably, various immune cells, including T cells, play a significant role in modulating macrophage polarization by releasing cytokines that influence macrophage maturation and function. Furthermore, other immune cells can also impact macrophage polarization in a T-cell-independent manner. Therefore, this review comprehensively examines macrophage polarization’s role in leishmaniasis and other immune cells’ potential involvement in this intricate process.

Activation of the renin–angiotensin system has been implicated in hypertension. Angiotensin (Ang) II is a potent proinflammatory mediator. The present study investigated the role of myeloid angiotensin type 1 receptor (AT1R) in control of macrophage phenotype in vitro and vascular injury in deoxycorticosterone acetate (DOCA)/salt hypertension. In human THP-1/macrophages, Ang II increased mRNA expressions of M1 cytokines and decreased M2 cytokine expressions. Overexpression of AT1R further increased Ang II-induced expressions of M1 cytokines and decreased M2 cytokines. Silenced AT1R reversed Ang II-induced changes in M1 and M2 cytokines. Ang II upregulated hypoxia-inducible factor (HIF)1α, toll-like receptor (TLR)4, and the ratio of pI κ B/I κ B, which were prevented by silenced AT1R. Silenced HIF1α prevented Ang II activation of the TLR4/NF κ B pathway. Furthermore, Ang II increased HIF1α via reactive oxygen species-dependent reduction in prolyl hydroxylase domain protein 2 (PHD2) expression. The expressions of AT1R and HIF1α and the ratio of pI κ B/I κ B were upregulated in the peritoneal macrophages of DOCA hypertensive mice, and the specific deletion of myeloid AT1R attenuated cardiac and vascular injury and vascular oxidative stress, reduced the recruitment of macrophages and M1 cytokine expressions, and improved endothelial function without significant reduction in blood pressure. Our results demonstrate that Ang II/AT1R controls the macrophage phenotype via stimulating the HIF1α/NF κ B pathway, and specific myeloid AT1R KO improves endothelial function, vascular inflammation, and injury in salt-sensitive hypertension. The results support the notion that myeloid AT1R plays an important role in the regulation of the macrophage phenotype, and dysfunction of this receptor may promote vascular dysfunction and injury in salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Acute and chronic inflammation are vital contributing factors to pulmonary diseases which can be triggered by exposure to occupational and man-made particles; however, there are no established treatments. One potential treatment shown to have anti-inflammatory capabilities is the dietary supplement docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid found in fish oil. DHA's anti-inflammatory mechanisms are unclear for particle-induced inflammation; therefore, this study evaluated DHA as a prophylactic treatment for semi-acute and chronic particle-induced inflammation in vivo. Balb/c mice were fed a control or 1% DHA diet and exposed to dispersion media, an inflammatory multi-walled carbon nanotube (MWCNT), or crystalline silica (SiO2) either once (semi-acute) or once a week for 4 weeks (chronic). The hypothesis was that DHA will decrease pulmonary inflammatory markers in response to particle-induced inflammation. Results indicated that DHA had a trending anti-inflammatory effect in mice exposed to MWCNT. There was a general decrease in inflammatory signals within the lung lavage fluid and upregulation of M2c macrophage gene expression in the spleen tissue. In contrast, mice exposed to SiO2 while on the DHA diet significantly increased most inflammatory markers. However, DHA stabilized the phagolysosomal membrane upon prolonged treatment. This indicated that DHA treatment may depend upon certain inflammatory particle exposures as well as the length of the exposure. [ABSTRACT FROM AUTHOR]

Activation of the renin–angiotensin system has been implicated in hypertension. Angiotensin (Ang) II is a potent proinflammatory mediator. The present study investigated the role of myeloid angiotensin type 1 receptor (AT1R) in control of macrophage phenotype in vitro and vascular injury in deoxycorticosterone acetate (DOCA)/salt hypertension. In human THP-1/macrophages, Ang II increased mRNA expressions of M1 cytokines and decreased M2 cytokine expressions. Overexpression of AT1R further increased Ang II-induced expressions of M1 cytokines and decreased M2 cytokines. Silenced AT1R reversed Ang II-induced changes in M1 and M2 cytokines. Ang II upregulated hypoxia-inducible factor (HIF)1α, toll-like receptor (TLR)4, and the ratio of pIκB/IκB, which were prevented by silenced AT1R. Silenced HIF1α prevented Ang II activation of the TLR4/NFκB pathway. Furthermore, Ang II increased HIF1α via reactive oxygen species-dependent reduction in prolyl hydroxylase domain protein 2 (PHD2) expression. The expressions of AT1R and HIF1α and the ratio of pIκB/IκB were upregulated in the peritoneal macrophages of DOCA hypertensive mice, and the specific deletion of myeloid AT1R attenuated cardiac and vascular injury and vascular oxidative stress, reduced the recruitment of macrophages and M1 cytokine expressions, and improved endothelial function without significant reduction in blood pressure. Our results demonstrate that Ang II/AT1R controls the macrophage phenotype via stimulating the HIF1α/NFκB pathway, and specific myeloid AT1R KO improves endothelial function, vascular inflammation, and injury in salt-sensitive hypertension. The results support the notion that myeloid AT1R plays an important role in the regulation of the macrophage phenotype, and dysfunction of this receptor may promote vascular dysfunction and injury in salt-sensitive hypertension.

The host immune response to an implanted biomaterial, particularly the phenotype of infiltrating macrophages, is a key determinant of biocompatibility and downstream remodeling outcome. The present study used a subcutaneous rat model to compare the tissue response, including macrophage phenotype, remodeling potential, and calcification propensity of a biologic scaffold composed of glutaraldehyde‐fixed bovine pericardium (GF‐BP), the standard of care for heart valve replacement, with those of an electrospun polycarbonate‐based supramolecular polymer scaffold (ePC‐UPy), urinary bladder extracellular matrix (UBM‐ECM), and a polypropylene mesh (PP). The ePC‐UPy and UBM‐ECM materials induced infiltration of mononuclear cells throughout the thickness of the scaffold within 2 days and neovascularization at 14 days. GF‐BP and PP elicited a balance of pro‐inflammatory (M1‐like) and anti‐inflammatory (M2‐like) macrophages, while UBM‐ECM and ePC‐UPy supported a dominant M2‐like macrophage phenotype at all timepoints. Relative to GF‐BP, ePC‐UPy was markedly less susceptible to calcification for the 180 day duration of the study. UBM‐ECM induced an archetypical constructive remodeling response dominated by M2‐like macrophages and the PP caused a typical foreign body reaction dominated by M1‐like macrophages. The results of this study highlight the divergent macrophage and host remodeling response to biomaterials with distinct physical and chemical properties and suggest that the rat subcutaneous implantation model can be used to predict in vivo biocompatibility and regenerative potential for clinical application of cardiovascular biomaterials. [ABSTRACT FROM AUTHOR]

Objective To observe the effects of Yiqi Huoxue Jiedu Fang (Qi-Benefiting, Blood-Activating, and Toxin-Eliminating Formula, YQHXJDF) on progression-free survival (PSF), quality of life and pattern changes of traditional Chinese medicine (TCM) in the treatment of platinum-resistant ovarian cancer, and its mechanism through regulating IL-6 level and macrophage phenotype. Methods A randomized controlled trial was conducted in 75 patients with platinum-resistant ovarian cancer with qi deficiency and blood stasis pattern. Both groups received standardized treatment of western medicine, on the basis of which the control group was given Chinese patent medicine-Xihuang Jiedu Jiaonang (Toxin-Eliminating Capsule with American Ginseng and Cow Bezoar, XHJDJN) orally, while the treatment group, YQHXJDF. The intervention was finished with end of the study or progression of the disease followed by death. The peripheral blood of the participants was collected, and the levels of IL-6 and M2 in macrophage percentage were detected at enrollment and 2 months after intervention with Pearson coefficient analysis. There was follow-up once every 2 months to evaluate the quality of life (QoL) and the changes of TCM pattern scores. Cox regression analysis was conducted to identify PFS risk factors. Results There was no statistically significant difference in TCM pattern scores, age, stage, M2 macrophage percentage and IL-6 level between the two groups. The median progression-free survival (mPFS) of the treatment group was 6 months [95% confidence interval (CI), 4.77-7.23], and the mPFS of the control group was 5 months (95% CI, 3.06-6.94). There was significant difference between the two groups. QoL and TCM pattern score were improved in both groups with no statistical significance between two groups. When IL-6 is lower than 5.5 ng/L, IL-6 level was negatively correlated with M2 macrophage percentage. IL-6 in the treatment group was increased after treatment, but there was no statistically significant difference in the control group before and after treatment; when IL-6 is higher than 5. 5 ng/L, the level of IL-6 was positively correlated with M2 macrophage percentage, and the levels of IL-6 in both groups were decreased after treatment. The quality of life in the treatment group was better after intervention than that before intervention. There was no statistically significant difference in the control group before and after treatment. Besides, the quality of life in the treatment group was better than that in the control group. The number of chemotherapy lines and M2 macrophage percentage were risk factors of PFS. Conclusion YQHXJDF could prolong the PFS of patients with advanced platinum-resistant ovarian cancer, improve the quality of life and TCM patterns. It could also improve the level of IL-6 to a certain extent and thus improve immune function. When IL-6 is too high, both YQHXJDF and XHJDJN can reduce the level of IL-6 in peripheral blood and alleviate immunosuppression. The changes of macrophage phenotype seems to influence the PFS. [ABSTRACT FROM AUTHOR]

In the intratracheal bleomycin (ITB) model of acute lung injury (ALI), macrophages are recruited to the lung and participate in the inflammation and resolution that follows injury. Macrophage origin is influential in determining activation; however, the specific phenotype of recruited and resident macrophages is not known. Inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of ALI; however, the effects of its inhibition are mixed. Here we examined how macrophage origin determines the phenotypic response to ALI. Further, we hypothesize cell specific iNOS is key to determining activation and recruitment. Using a chimeric mouse approach, we have identified recruited and resident macrophage populations. We also used the chimeric mouse approach to create either pulmonary or bone marrow NOS2−/− mice and systemically inhibited iNOS via 1400 W. We evaluated macrophage populations at the peak of inflammation (8 days) and the beginning of resolution (15 days) following ITB. These studies demonstrate tissue resident macrophages adopt a M2 phenotype specifically, but monocyte originated macrophages activate along a spectrum. Additionally, we demonstrated that monocyte originating macrophage derived iNOS is responsible for recruitment to the lung during the inflammatory phase. Further, we show that macrophage activation is dependent upon cellular origin. Finally, these studies suggest pulmonary derived iNOS is detrimental to the lung following ITB. In conclusion, macrophage origin is a key determinant in response to ALI and iNOS is central to recruitment and activation. [ABSTRACT FROM AUTHOR]

The effects of feruloylated arabinoxylan (AX) on typically activated inflammatory macrophages (M1) and alternatively anti-inflammatory macrophages (M2) and its possible mechanisms were investigated. The results revealed that feruloylated AX was composed of 37.63% arabinose and 52.23% xylose, with a weight-average molecular weight of 1.1374 × 104 Da, and bound ferulic acid content of 10.84 mg/g. Besides, feruloylated AX (50–1000 μg/mL) markedly downregulated the mRNA expressions of NO, IL-1β, TNF-α, IL-6, and IL-23a, and reduced the phosphorylation levels of p38, ERK, and JNK in M1. In contrast, the mRNA expressions of Arg-1, Mrc-1, and CCL22 were significantly upregulated by feruloylated AX (50–1000 μg/mL), and the phosphorylation level of AKT was significantly increased in M2. Overall, our results indicated that feruloylated AX could have an inhibitory or a promoting effect on already activated macrophages, and MAPK or PI3K signaling pathways might be involved in this regulation. [Display omitted] • Feruloylated AX had no effects on non-polarized macrophages. • Feruloylated AX inhibited M1-macrophage activation via MAPK signaling pathways. • Feruloylated AX enhanced M2-macrophage polarization via PI3K signaling pathways. [ABSTRACT FROM AUTHOR]

Phospholipases A2 (PLA2s) catalyze hydrolysis of the sn-2 substituent from glycerophospholipids to yield a free fatty acid (i.e., arachidonic acid), which can be metabolized to pro- or anti-inflammatory eicosanoids. Macrophages modulate inflammatory responses and are affected by Ca2+-independent phospholipase A2 (PLA2)β (iPLA2β). Here, we assessed the link between iPLA2β-derived lipids (iDLs) and macrophage polarization. Macrophages from WT and KO (iPLA2β−/−) mice were classically M1 pro-inflammatory phenotype activated or alternatively M2 anti-inflammatory phenotype activated, and eicosanoid production was determined by ultra-performance LC ESI-MS/MS. As a genotypic control, we performed similar analyses on macrophages from RIP.iPLA2β.Tg mice with selective iPLA2β overexpression in β-cells. Compared with WT, generation of select pro-inflammatory prostaglandins (PGs) was lower in iPLA2β−/−, and that of a specialized pro-resolving lipid mediator (SPM), resolvin D2, was higher; both changes are consistent with the M2 phenotype. Conversely, macrophages from RIP.iPLA2β.Tg mice exhibited an opposite landscape, one associated with the M1 phenotype: namely, increased production of pro-inflammatory eicosanoids (6-keto PGF1α, PGE2, leukotriene B4) and decreased ability to generate resolvin D2. These changes were not linked with secretory PLA2 or cytosolic PLA2α or with leakage of the transgene. Thus, we report previously unidentified links between select iPLA2β-derived eicosanoids, an SPM, and macrophage polarization. Importantly, our findings reveal for the first time that β-cell iPLA2β-derived signaling can predispose macrophage responses. These findings suggest that iDLs play critical roles in macrophage polarization, and we posit that they could be targeted therapeutically to counter inflammation-based disorders.

In the intratracheal bleomycin (ITB) model of acute lung injury (ALI), macrophages are recruited to the lung and participate in the inflammation and resolution that follows injury. Macrophage origin is influential in determining activation; however, the specific phenotype of recruited and resident macrophages is not known. Inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of ALI; however, the effects of its inhibition are mixed. Here we examined how macrophage origin determines the phenotypic response to ALI. Further, we hypothesize cell specific iNOS is key to determining activation and recruitment. Using a chimeric mouse approach, we have identified recruited and resident macrophage populations. We also used the chimeric mouse approach to create either pulmonary or bone marrow NOS2−/− mice and systemically inhibited iNOS via 1400 W. We evaluated macrophage populations at the peak of inflammation (8 days) and the beginning of resolution (15 days) following ITB. These studies demonstrate tissue resident macrophages adopt a M2 phenotype specifically, but monocyte originated macrophages activate along a spectrum. Additionally, we demonstrated that monocyte originating macrophage derived iNOS is responsible for recruitment to the lung during the inflammatory phase. Further, we show that macrophage activation is dependent upon cellular origin. Finally, these studies suggest pulmonary derived iNOS is detrimental to the lung following ITB. In conclusion, macrophage origin is a key determinant in response to ALI and iNOS is central to recruitment and activation.

Osteoarthritis (OA) is a degenerative joint disease characterized by obscure etiology and unsatisfactory therapeutic outcomes, making the development of new efficient therapies urgent. Superfluous reactive oxygen species (ROS) have historically been considered one of the crucial factors inducing the pathological progression of OA. Ultrasmall Prussian blue nanoparticles (USPBNPs), approximately sub-5 nm in size, are developed by regulating the configuration of polyvinylpyrrolidone chains. USPBNPs display an excellent ROS eliminating capacity and catalase-like activity, capable of decomposing hydrogen peroxide (H 2 O 2 ) into O 2 . The anti-inflammatory mechanism of USPBNPs can be attributed to repolarizing macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype by decreasing the ROS levels accompanied by O 2 improvement. Additionally, USPBNPs exhibit an exciting therapeutic efficiency against OA, comparable to that of hydrocortisone in vivo. This study not only develops a new therapeutic agent for OA but also offers an estimable insight into the application of the nanozyme.

The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl4). Flow cytometry of non-parenchymal liver cells obtained from CCl4-treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8+ T-lymphocytes and with an increase in ICOSL expression involving CD11bhigh/F4-80+ hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl4-treated ICOS knockout (ICOS-/-) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8+ T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl4-treated ICOS-/- mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8+ T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury. [ABSTRACT FROM AUTHOR]

Mounting evidence argues for the significant impact of sex in numerous cardiac pathologies, including myocarditis. Macrophage polarization and activation of cardiac fibroblasts play a key role in myocardial inflammation and remodeling. However, the role of sex in these processes is still poorly understood. In this study, we investigated sex-specific alterations in the polarization of murine bone marrow-derived macrophages (BMMs) and the polarization-related changes in fibroblast activation. Cultured male and female murine BMMs from C57/BL6J mice were polarized into M1 (LPS) and M2 (IL-4/IL-13) macrophages. Furthermore, male and female cardiac fibroblasts from C57/BL6J mice were activated with TNF-α, TGF-β, or conditioned medium from M1 BMMs. We found a significant overexpression of M1 markers (c-fos, NFκB, TNF-α, and IL-1β) and M2 markers (MCP-1 and YM1) in male but not female activated macrophages. In addition, the ROS levels were higher in M1 male BMMs, indicating a stronger polarization. Similarly, the pro-fibrotic markers TGF-β and IL-1β were expressed in activated cardiac male fibroblasts at a significantly higher level than in female fibroblasts. In conclusion, the present study provides strong evidence for the male-specific polarization of BMMs and activation of cardiac fibroblasts in an inflammatory environment. The data show an increased inflammatory response and tissue remodeling in male mice. [ABSTRACT FROM AUTHOR]

The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl4). Flow cytometry of non-parenchymal liver cells obtained from CCl4-treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8+ T-lymphocytes and with an increase in ICOSL expression involving CD11bhigh/F4-80+ hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl4-treated ICOS knockout (ICOS-/-) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8+ T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl4-treated ICOS-/- mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8+ T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury.

Mounting evidence argues for the significant impact of sex in numerous cardiac pathologies, including myocarditis. Macrophage polarization and activation of cardiac fibroblasts play a key role in myocardial inflammation and remodeling. However, the role of sex in these processes is still poorly understood. In this study, we investigated sex-specific alterations in the polarization of murine bone marrow-derived macrophages (BMMs) and the polarization-related changes in fibroblast activation. Cultured male and female murine BMMs from C57/BL6J mice were polarized into M1 (LPS) and M2 (IL-4/IL-13) macrophages. Furthermore, male and female cardiac fibroblasts from C57/BL6J mice were activated with TNF-α, TGF-β, or conditioned medium from M1 BMMs. We found a significant overexpression of M1 markers (c-fos, NFκB, TNF-α, and IL-1β) and M2 markers (MCP-1 and YM1) in male but not female activated macrophages. In addition, the ROS levels were higher in M1 male BMMs, indicating a stronger polarization. Similarly, the pro-fibrotic markers TGF-β and IL-1β were expressed in activated cardiac male fibroblasts at a significantly higher level than in female fibroblasts. In conclusion, the present study provides strong evidence for the male-specific polarization of BMMs and activation of cardiac fibroblasts in an inflammatory environment. The data show an increased inflammatory response and tissue remodeling in male mice.

BACKGROUND: Biomaterials derived from extracellular matrix have been successfully applied in the field of tissue engineering regeneration. In recent years, great attention has been paid to the effect of biomaterials on the phenotypic polarization of macrophages. OBJECTIVE: To investigate the regulatory effects of decellularized cartilage extracellular matrix (DCM) and pepsin-treated decellularized cartilage extracellular matrix (PDCM) on phenotypic polarization of macrophages. METHODS: The DCM of the pig was prepared by physical comminution, repeated freeze-thaw and differential centrifugation. The biodegradation product (PDCM) was obtained by dissolving it in pepsin solution. Mouse macrophage cell line RAW264.7 was divided into five groups. In the control group, complete macrophage culture medium was added. In the M1 positive control group, lipopolysaccharide + interferon γ solution was added. In the M2 positive control group, interleukin 4 solution was added. In the PDCM group, PDCM solution was added. In the pepsin group, pepsin solution was added. After 18 hours of culture, immunofluorescence staining for CD86 (M1 type macrophages) and CD206 (M2 type macrophages) was performed. In addition, mouse macrophage cell line RAW264.7 was divided into six groups: control group, M1 positive control group, M2 positive control group, pepsin group, DCM coating group and PDCM coating group. After 24 hours of culture, CD86 and CD206 were detected by flow cytometry. RESULTS AND CONCLUSION: (1) Immunofluorescence results showed that in the PDCM group, induced CD86 expression ratio was approximately 0.13; induced CD206 expression ratio was approximately 0.5. (2) Flow cytometry results showed that DCM induced CD86 (20.1%) and CD206 (28.8%) expression in macrophages; PDCM only induced CD206 expression (23.2%). (3) The results showed that DCM and its biodegradation products could promote M2 polarization of macrophages. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease, including atherosclerosis, has an inflammatory background on a molecular scale. In the immune system, various factors activate macrophages, which ultimately lead to various macrophage activities in inflammatory and non-inflammatory conditions. The aim of the present study was to investigate the effect of eight weeks of combined training on serum macrophage phenotype after cardiac arrhythmias and coronary artery bypass graft surgery. Methods: The present study was a quasi-experimentalstudy performed in the Heart Rehabilitation Center of Afshar Hospital in Yazd. 20 male patients after coronary artery bypass graft surgery were divided into the control and combined exercise groups. Functional capacity, body mass index, muscle strength, and waist-to-hip ratio were estimated before training.The combined program was included aerobic and resistance training for eight weeks, three sessions per week. Aerobic training was performed for 15-20 minutes with maximum intensity of 50-80% of maximum heart rate and resistance training program included three upper limb and two lower limb movements with three sets and 10 repetitions. Blood samples were taken before and after eight weeks and macrophage phenotypes were measured by the ELISA method. Data were analyzed through independent t-test and paired t-test using SPSS Inc., Chicago, IL; version 16 software. Results: The combined exercise resulted in a significant decrease in the M1 macrophage (P

Jorge Rodrigues de Sousa,1,2 Pedro Fernando Da Costa Vasconcelos,2,3 Juarez Antonio Simões Quaresma1–41Tropical Medicine Center, Federal University of Pará, Belém, PA, Brazil; 2Evandro Chagas Institute, Ministry of Health, Ananindeua, PA, Brazil; 3Center of Biological and Health Sciences, State University of Pará, Belém, PA, Brazil; 4School of Medicine, São Paulo University, São Paulo, SP, BrazilCorrespondence: Juarez Antonio Simões QuaresmaTropical Medicine Center, Federal University of Pará, Av. Generalissimo Deodoro 92, Umarizal, Belém 66055-240, PA, BrazilEmail juarez.quaresma@gmail.comAbstract: Macrophages are a functionally heterogeneous group of cells with specialized functions depending not only on their subgroup but also on the function of the organ or tissue in which the cells are located. The concept of macrophage phenotypic heterogeneity has been investigated since the 1980s, and more recent studies have identified a diverse spectrum of phenotypic subpopulations. Several types of macrophages play a central role in the response to infectious agents and, along with other components of the immune system, determine the clinical outcome of major infectious diseases. Here, we review the functions of various macrophage phenotypic subpopulations, the concept of macrophage polarization, and the influence of these cells on the evolution of infections. In addition, we emphasize their role in the immune response in vivo and in situ, as well as the molecular effectors and signaling mechanisms used by these cells. Furthermore, we highlight the mechanisms of immune evasion triggered by infectious agents to counter the actions of macrophages and their consequences. Our aim here is to provide an overview of the role of macrophages in the pathogenesis of critical transmissible diseases and discuss how elucidation of this relationship could enhance our understanding of the host–pathogen association in organ-specific immune responses.Keywords: macrophage, macrophage phenotype, macrophage activation, infections, infectious diseases