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The interactions between vascular cells, especially endothelial cells, and macrophages play a pivotal role in maintaining the subtle balance of vascular biology, which is crucial for angiogenesis in both healthy and diseased states. These cells are central to ensuring a harmonious balance between tissue repair and preventing excessive angiogenic activity, which could lead to pathological conditions. Recent advances in sophisticated genetic engineering vivo models and novel sequencing approaches, such as single-cell RNA-sequencing, in immunobiology have significantly enhanced our understanding of the gene expression and behavior of macrophages. These insights offer new perspectives on the role macrophages play not only in development but also across various health conditions. In this review, we explore the complex interactions between multiple types of macrophages and endothelium, focusing on their impact on new blood vessel formation. By understanding these intricate interactions, we aim to provide insights into new methods for managing angiogenesis in various diseases, thereby offering hope for the development of novel therapeutic approaches., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma is one of the most common cancers worldwide. Despite progress in treatment, recurrence after radical treatment is common, and the prognosis remains poor for patients with advanced disease. Therefore, there is a need to identify prognostic and predictive factors for the response to therapy or more intensive surveillance or treatment. Because the tumor microenvironment plays a crucial role in the development of cancer and metastasis, it is a crucial need to understand processes that are involved in carcinogenesis. Within the microenvironment, several immune cells with different roles are present. One of the most important of these is tumor-associated macrophages. These cells may exert either antitumor or protumor roles. Several studies have suggested that tumor-associated macrophages can be used as prognostic markers. Furthermore, they may be involved in resistance to immunotherapy or systemic treatment. As they play an important role in cancer development, tumor-associated macrophages are also a good target for therapy. In this review, we briefly summarize recent progress on knowledge regarding the basic molecular characteristics, impact on prognosis and potential clinical implications of tumor-associated macrophages in hepatocellular carcinoma., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The liver is a vital organ that continuously adapts to a wide and dynamic diversity of self-antigens and xenobiotics. This involves the active contribution of immune cells, particularly by the liver-resident macrophages, the Kupffer cells (KCs), which exert a variety of central functions in liver homeostasis and disease. As such, KCs interact with their microenvironment to shape the hepatic cellular landscape, control gut-derived signal integration, and modulate metabolism. On injury, the rapid recruitment of bone marrow monocyte-derived macrophages alters this status quo and, when unrestrained, drastically compromises liver homeostasis, immune surveillance, and tissue organization. Several factors determine the functional roles of liver macrophages in these processes, such as their ontogeny, activation/polarization profile and, importantly, spatial distribution within the liver. Loss of tolerance and adaptability of the hepatic immune environment may result in persistent inflammation, hepatic fibrosis, cirrhosis, and a tumorigenic niche promoting liver cancer. In this review, we aim at providing the most recent breakthroughs in our understanding of liver macrophage biology, particularly their diversity and adaptability in the hepatic spatiotemporal context, as well as on potential therapeutic interventions that may hold the key to tackling remaining clinical challenges of varying etiologies in hepatology., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: The colonic epithelium is the most rapidly renewing tissue in the body and is organized into a single cell layer of invaginations called crypts. Crypt renewal occurs through Lgr5 + gut stem cells situated at the crypt base, which divide, produce daughter cells that proliferate, migrate, differentiate into all the cells required for normal gut function, and are finally shed into the crypt lumen. In health, this rapid renewal helps maintain barrier function next to the hostile gut microbial luminal environment. Inflammation results in an influx of immune cells including inflammatory M1 macrophages into the gut mucosa next to the crypt epithelium, but the direct effect of macrophages on crypt regeneration and renewal are poorly understood., Methods: Using an in vitro macrophage-crypt coculture model, we show that homeostatic M2 macrophages and inflammatory M1 macrophages confer different effects on the crypt epithelium., Results: Both M1 and M2 increase crypt cell proliferation, with M2 macrophages requiring physical contact with the crypt epithelium, whereas M1 macrophages exert their effect through a secreted factor. Only M1 macrophages reduce goblet and Tuft cell numbers and increase Lgr5 + crypt stem cell numbers, all dependent on physical contact with the crypt epithelium. Further studies showed that M1 macrophages increase the Wnt signaling pathways cyclin D1 and LEF1 through physical contact rather than a secreted factor., Conclusions: These findings highlight the importance of understanding distinct cellular interactions and direct dialogue between cells and increase our understanding of the contribution of different immune cell subtypes on crypt cell biology during inflammation., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Vitamin D plays a crucial role in preventing atherosclerosis and in the regulation of macrophage function. This review aims to provide a comprehensive summary of the clinical evidence regarding the impact of vitamin D on atherosclerotic cardiovascular disease, atherosclerotic cerebrovascular disease, peripheral arterial disease, and associated risk factors. Additionally, it explores the mechanistic studies investigating the influence of vitamin D on macrophage function in atherosclerosis. Numerous findings indicate that vitamin D inhibits monocyte or macrophage recruitment, macrophage cholesterol uptake, and esterification. Moreover, it induces autophagy of lipid droplets in macrophages, promotes cholesterol efflux from macrophages, and regulates macrophage polarization. This review particularly focuses on analyzing the molecular mechanisms and signaling pathways through which vitamin D modulates macrophage function in atherosclerosis. It claims that vitamin D has a direct inhibitory effect on the formation, adhesion, and migration of lipid-loaded monocytes, thus exerting anti-atherosclerotic effects. Therefore, this review emphasizes the crucial role of vitamin D in regulating macrophage function and preventing the development of atherosclerosis., (© 2024 Wiley‐VCH GmbH.)

Obesity is characterized by adipose tissue expansion, extracellular matrix remodelling and unresolved inflammation that contribute to insulin resistance and fibrosis. Adipose tissue macrophages represent the most abundant class of immune cells in adipose tissue inflammation and could be key mediators of adipocyte dysfunction and fibrosis in obesity. Although macrophage activation states are classically defined by the M1/M2 polarization nomenclature, novel studies have revealed a more complex range of macrophage phenotypes in response to external condition or the surrounding microenvironment. Here, we discuss the plasticity of adipose tissue macrophages (ATMs) in response to their microenvironment in obesity, with special focus on macrophage infiltration and polarization, and their contribution to adipose tissue fibrosis. A better understanding of the role of ATMs as regulators of adipose tissue remodelling may provide novel therapeutic strategies against obesity and associated metabolic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The link between ferroptosis, a form of cell death mediated by iron and acute kidney injury (AKI) is recently gaining widespread attention. However, the mechanism of the crosstalk between cells in the pathogenesis and progression of acute kidney injury remains unexplored. In our research, we performed a non-negative matrix decomposition (NMF) algorithm on acute kidney injury single-cell RNA sequencing data based specifically focusing in ferroptosis-associated genes. Through a combination with pseudo-time analysis, cell-cell interaction analysis and SCENIC analysis, we discovered that proximal tubular cells, macrophages, and fibroblasts all showed associations with ferroptosis in different pathways and at various time. This involvement influenced cellular functions, enhancing cellular communication and activating multiple transcription factors. In addition, analyzing bulk expression profiles and marker genes of newly defined ferroptosis subtypes of cells, we have identified crucial cell subtypes, including Egr1 + PTC-C1, Jun + PTC-C3, Cxcl2 + Mac-C1 and Egr1 + Fib-C1. All these subtypes which were found in AKI mice kidneys and played significantly distinct roles from those of normal mice. Moreover, we verified the differential expression of Egr1, Jun, and Cxcl2 in the IRI mouse model and acute kidney injury human samples. Finally, our research presented a novel analysis of the crosstalk of proximal tubular cells, macrophages and fibroblasts in acute kidney injury targeting ferroptosis, therefore, contributing to better understanding the acute kidney injury pathogenesis, self-repairment and acute kidney injury-chronic kidney disease (AKI-CKD) progression., (© 2024. The Author(s).)

Macrophages play a wide range of roles in resolving the inflammatory damage that underlies many medical conditions and have the ability to adopt different phenotypes in response to different environmental stimuli. Categorising macrophage phenotypes exactly is a difficult task, and there is disparity in the literature around the optimal nomenclature to describe these phenotypes; however, what is clear is that macrophages can exhibit both pro- and anti-inflammatory behaviours dependent upon their phenotype, rendering mathematical models of the inflammatory response potentially sensitive to their description of the macrophage populations that they incorporate. Many previous models of inflammation include a single macrophage population with both pro- and anti-inflammatory functions. Here, we build upon these existing models to include explicit descriptions of distinct macrophage phenotypes and examine the extent to which this influences the inflammatory dynamics that the models emit. We analyse our models via numerical simulation in MATLAB and dynamical systems analysis in XPPAUT, and show that models that account for distinct macrophage phenotypes separately can offer more realistic steady state solutions than precursor models do (better capturing the anti-inflammatory activity of tissue resident macrophages), as well as oscillatory dynamics not previously observed. Finally, we reflect on the conclusions of our analysis in the context of the ongoing hunt for potential new therapies for inflammatory conditions, highlighting manipulation of macrophage polarisation states as a potential therapeutic target., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)

Synovial tissue-resident macrophages (STRMs) maintain normal joint homeostasis in a steady state. However, it is unclear whether STRMs still play homeostatic roles or change the functions in the joint of rheumatoid arthritis (RA), where infiltrating peripheral blood monocyte-derived macrophages (PBMoMs) play proinflammatory roles. In the present study, we examined changes in the phenotypes and functions of STRMs in response to RA-related stimuli in vitro . STRMs were prepared from non-inflammatory osteoarthritis (OA) joint synovium, which is histologically indistinguishable from normal joint synovium. PBMoMs were prepared and used for comparison. After stimulation with plate-bound IgG, which mimics anti-citrullinated protein antibody immunocomplex formed in RA joints, or with combinations of RA-related inflammatory mediators, namely tumor necrosis factor-α (TNF-α) and prostaglandin E2 or interferon-γ, PBMoMs downregulated surface markers and genes associated with anti-inflammatory macrophages, and upregulated cytokine and marker genes of proinflammatory macrophages in RA. On the other hand, STRMs hardly changed the expression of surface molecules and marker genes but altered the pattern of cytokine gene expression after stimulation like PBMoMs. Furthermore, in vitro stimulated STRMs promote proinflammatory functions of cocultured synovial fibroblasts. Thus, STRMs might play proinflammatory roles in RA joints, while maintaining their phenotypes in the steady state.

The knowledge of bone biology has undergone major advances in recent decades. In bone, resorbing osteoclasts have classically been described as tissue-resident macrophages, however, it is currently known that a new subtype of macrophages, called OsteoMacs, are specialised bone-resident macrophages, which, depending on certain conditions, may play an important role not only in bone homeostasis, but also in promoting pro-anabolic functions or in creating an inflammatory environment. There is growing evidence that these osteal macrophages may influence the development of bone-loss diseases. It is essential to understand the biological bases underlying bone physiological processes to search for new therapeutic targets for bone-loss diseases, such as osteoporosis, rheumatoid arthritis, or even periodontal disease. This narrative review provides an update on the origin, characterisation, and possible roles of osteoMacs in bone biology. Finally, the potential clinical applications of this new cell in bone-loss disorders are discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Tumor-associated macrophages within the tumor microenvironment play an immunosuppressive role by promoting tumor growth and immune evasion. Macrophages are highly plastic and can be stimulated to adopt an anti-tumor M1 phenotype. In this study, we used microcystin-LR (MC-LR), a cyclic heptapeptide produced by cyanobacteria, to induce in vitro macrophage innate immunity and transition into the anti-tumor M1 phenotype. MC-LR was also tested in vivo in a mouse model of colorectal cancer. An intraperitoneal injection of MC-LR increased the proportion of CD86⁺ M1 macrophages and triggered the maturation of CD11c⁺ dendritic cells within tumor tissues. MC-LR combined with the chemotherapeutic drug oxaliplatin significantly inhibited tumor growth in vivo. Flow cytometry analysis revealed increased infiltration of activated cytotoxic (CD8⁺, PD-1⁺) T-cells and anti-tumor cytokines (IFNγ and Granzyme B) in the tumor tissues of the combination therapy group, suggesting that this may be the primary mechanism behind the anti-tumor effect of the combination treatment. These findings indicate that MC-LR regulates the immune stimulation of macrophage polarization and dendritic cell maturation, effectively reversing tumor immunosuppression, activating an anti-tumor immune response, and enhancing tumor therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The resolution of inflammation is an active process leading to the restoration of tissue homeostasis. A critical step in the initiation of this process is the elimination of apoptotic immune cells by macrophages. This well-organized process, called efferocytosis, involves four different steps, namely the attraction of macrophages to the site where the cells die, the recognition of apoptotic cells, their internalization and their digestion leading to the activation of different metabolic pathways. All these steps are responsible for the reprogramming of macrophages towards a pro-resolving profile. Efferocytic macrophages produce several factors involved in the resolution of inflammation. These factors include lipids (i.e., specialized pro-resolving mediators such as lipoxins), and proteins (e.g., IL-10 or TGF-β). Here, we describe the different steps of efferocytosis and the mechanisms responsible for both macrophage reprogramming and the release of pro-resolving factors. These factors may represent a new therapeutic approach, called resolution therapy., (© 2024 médecine/sciences – Inserm.)

Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable and detrimental functions. Early in atherogenesis, macrophages can clear cytotoxic lipoproteins and dead cells, preventing cytotoxicity. Efferocytosis - the efficient clearance of dead cells by macrophages - is crucial for preventing secondary necrosis and stimulating the release of anti-inflammatory cytokines. In addition, macrophages can promote tissue repair and proliferation of vascular smooth muscle cells, thereby increasing plaque stability. However, advanced atherosclerotic plaques contain large numbers of pro-inflammatory macrophages that secrete matrix-degrading enzymes, induce death in surrounding cells and contribute to plaque destabilization and rupture. Importantly, macrophages in the plaque can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. Regulated necrosis has an important role in the formation and expansion of the necrotic core during plaque progression, and several triggers for necrosis are present within atherosclerotic plaques. This Review focuses on the various forms of programmed macrophage death in atherosclerosis and the pharmacological interventions that target them as a potential means of stabilizing vulnerable plaques and improving the efficacy of currently available anti-atherosclerotic therapies., (© 2024. Springer Nature Limited.)

Background and Objectives : Pelvic floor muscles (PFM) play a core role in defecation and micturition. Weakening of PFM underlies urogynecological disorders such as pelvic organ prolapse and stress urinary incontinence. Vaginal delivery damages PFM. Muscle trauma implies an inflammatory response mediated by myeloid cells, essential for subsequent recovery. Molecular signaling characterizing the pro-inflammatory phase shifts M1 macrophages to M2 macrophages, which modulate muscle repair. The present study aimed to evaluate histological characteristics and the presence of M1 and M2 macrophages in bulbospongiosus (Bsm) and pubococcygeus muscles (Pcm). Materials and Methods : Muscles from young nulliparous (N) and multiparous rabbits on postpartum days three (M3) and twenty (M20) were excised and histologically processed to measure the myofiber cross-sectional area (CSA) and count the centralized myonuclei in hematoxylin-eosinstained sections. Using immunohistochemistry, M1 and M2 macrophages were estimated in muscle sections. Kruskal-Wallis or one-way ANOVA testing, followed by post hoc tests, were conducted to identify significant differences ( p < 0.05). Results : The myofiber CSA of both the Bsm and Pcm of the M3 group were more extensive than those of the N and M20 groups. Centralized myonuclei estimated in sections from both muscles of M20 rabbits were higher than those of N rabbits. Such histological outcomes matched significant increases in HLA-DR immunostaining in M3 rabbits with the CD206 immunostaining in muscle sections from M20 rabbits. Conclusions : A shift from the pro- to anti-inflammatory phase in the bulbospongiosus and pubococcygeus muscles of multiparous rabbits matches with centralized myonuclei, suggesting the ongoing regeneration of muscles.

Macrophages are vital tissue components involved in organogenesis, maintaining homeostasis, and responses to disease. Mouse models have significantly improved our understanding of macrophages. Further investigations into the characteristics and development of human macrophages are crucial, considering the substantial anatomical and physiological distinctions between mice and humans. Despite challenges in human macrophage research, recent studies are shedding light on the ontogeny and function of human macrophages. In this opinion, we propose combinations of cutting-edge approaches to examine the diversity, development, niche, and function of human tissue-resident macrophages. These methodologies can facilitate our exploration of human macrophages more efficiently, ideally providing new therapeutic avenues for macrophage-relevant disorders., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Macrophages, a heterogeneous population of innate immune cells, exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases. The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects, inducing insulin resistance through increased inflammation, impaired thermogenesis, and adipose tissue fibrosis. Meanwhile, adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis, facilitating the clearance of dead adipocytes, and promoting mitochondrial transfer. Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions. Recently, the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology. In this review, we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity, as well as explore the potential of drug delivery systems targeting macrophages, aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases., (© 2023. Higher Education Press.)

Objectives: This study aimed to investigate the effect of calcitonin gene-related peptide (CGRP) on the temporal alteration of macrophage phenotypes and macrophage-regulated angiogenesis duringearlybonehealing and preliminarily elucidate the mechanism., Methods: In vivo, the rat mandibular defect models were established with inferior alveolar nerve transection (IANT) or CGRP receptor antagonist injection. Radiographicandhistologic assessments for osteogenesis, angiogenesis, and macrophage phenotypic alteration within bone defects were performed. In vitro, the effect and mechanism of CGRP on macrophage polarization and phenotypic alteration were analyzed. Then the conditioned medium (CM) from CGRP-treated M1 or M2 macrophages was used to culture human umbilical vein endothelial cells (HUVECs), and the CGRP's effect on macrophage-regulated angiogenesis was detected., Results: Comparable changes following IANT and CGRP blockade within bone defects were observed, including the suppression of early osteogenesis and angiogenesis, the prolonged M1 macrophage infiltration and the prohibited transition toward M2 macrophages around vascular endothelium. In vitro experiments showed that CGRP promoted M2 macrophage polarization while upregulating the expression of interleukin 6 (IL-6), a major cytokine that facilitates the transition from M1 to M2-dominant stage, in M1 macrophages via the activation of Yes-associated protein 1. Moreover, CGRP-treated macrophage-CM showed an anabolic effect on HUVECs angiogenesis compared with macrophage-CM and might prevail over the direct effect of CGRP on HUVECs., Conclusions: Collectively, our results reveal the effect of CGRP on M1 to M2 macrophage phenotypic alteration possibly via upregulating IL-6 in M1 macrophages, and demonstrate the macrophage-regulated pro-angiogenic potential of CGRP in early bone healing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cardiac resident macrophages (CRMs) are integral components of the heart and play significant roles in cardiac development, steady-state, and injury. Advances in sequencing technology have revealed that CRMs are a highly heterogeneous population, with significant differences in phenotype and function at different developmental stages and locations within the heart. In addition to research focused on diseases, recent years have witnessed a heightened interest in elucidating the involvement of CRMs in heart development and the maintenance of cardiac function. In this review, we primarily concentrated on summarizing the developmental trajectories, both spatial and temporal, of CRMs and their impact on cardiac development and steady-state. Moreover, we discuss the possible factors by which the cardiac microenvironment regulates macrophages from the perspectives of migration, proliferation, and differentiation under physiological conditions. Gaining insight into the spatiotemporal heterogeneity and regulatory mechanisms of CRMs is of paramount importance in comprehending the involvement of macrophages in cardiac development, injury, and repair, and also provides new ideas and therapeutic methods for treating heart diseases., (© 2024 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The temporal and spatial pattern of microglia colonization and vascular infiltration of the nervous system implies critical associated roles in early stages of nervous system development. Adding to existing reviews that cover a broad spectrum of the various roles of microglia during brain development, the current review will focus on the developmental ontogeny and interdependency between the colonization of the nervous system with yolk sac derived macrophages and vascularization. Gaining a better understanding of the timing and the interdependency of these two processes will significantly contribute to the interpretation of data generated regarding alterations in either process during early development. Additionally, such knowledge should provide a framework for understanding the influence of the early gestational environmental and the impact of genetics, disease, disorders, or exposures on the early developing nervous system and the potential for long-term and life-time effects.

Macrophages are innate immune cells with multiple functions such as phagocytosis, cytokine production, and antigen presentation. Since macrophages play critical roles in some bacterial infectious diseases in cattle, including tuberculosis, paratuberculosis, and brucellosis, the in vitro culturing of bovine macrophages is useful for evaluating host-pathogen interactions at the cellular and molecular levels. We have previously reported the establishment of two immortalized bovine liver sinusoidal cell lines, endothelial B46 cells and myofibroblast-like A26 cells (Cell Biology International, 40, 1372-1379, 2016). In this study, we investigated the use of these cell lines as feeder cells that support the proliferation of bovine blood-derived macrophages (BBMs). Notably, the B46 cell line efficiently acts as feeder cells for the propagation of BBMs. Compared with primary cultured vascular endothelial cells, the infinite proliferation ability of B46 cells is more beneficial for preparing confluent feeder layers. In conclusion, this study provides a simple and efficient protocol for the isolation and propagation of BBMs using a primary mixed culture of bovine whole blood with B46 feeder cells. Isolated BBMs are expected to be useful for developing in vitro models for studying the interactions between bovine pathogens and host immune cells., (© 2023 International Federation of Cell Biology.)

In acute inflammatory demyelinating polyneuropathy (AIDP), myelin vesiculation mediated by complement activation contributes to nerve injury. Macrophage infiltration of the spinal roots has been demonstrated in AIDP, but its pathological significance remains uncertain. The present study aimed to investigate the role of macrophages in the pathogenic sequence of AIDP. A rabbit model of AIDP was induced by immunization with galactocerebroside. Immunostaining was performed to localize the macrophages and myelin injury. The rabbit developed tetraparesis with electrophysiological and pathological features of peripheral nerve demyelination. Immunostaining demonstrated colocalization of IgG antibodies, complement deposition and myelin injury apart from macrophages. Immunostaining and electron microscopy showed myelin injury preceded macrophage infiltration. There was significant disruption of voltage-gated sodium channel clusters at the nodes of Ranvier in the spinal roots. Macrophages acted may as scavengers to remove myelin debris following complement activation-mediated demyelination in the AIDP rabbit. Lesions at the node of Ranvier contribute to conduction failure and muscle weakness., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Single-cell profiling of prenatal samples reveals multiple macrophage types and states, including microglia-like cells in non-neuronal tissues.

Macrophages play a crucial role in regulating wound healing, as they undergo a transition from the proinflammatory M1 phenotype to the proliferative M2 phenotype, ultimately contributing to a favorable outcome. However, in hyperglycemic and hyper-reactive oxygen species environments, the polarization of macrophages becomes dysregulated, hindering the transition from the inflammatory to proliferative phase and consequently delaying the wound healing process. Consequently, regulating macrophage polarization is often regarded as a potential target for the treatment of diabetic wounds. The role of macrophages in wound healing and the changes in macrophages in diabetic conditions were discussed in this review. After that, we provide a discussion of recent therapeutic strategies for diabetic wounds that utilize macrophage polarization. Furthermore, this review also provides a comprehensive summary of the efficacious treatment strategies aimed at enhancing diabetic wound healing through the regulation of macrophage polarization. By encompassing a thorough understanding of the fundamental principles and their practical implementation, the advancement of treatment strategies for diabetic wounds can be further facilitated., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Neovascular age-related macular degeneration causes vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Cx3cr1 -/- mice display alterations in non-classical monocytes and microglia with increased CNV size, suggesting that non-classical monocytes may inhibit CNV formation. NR4A1 is a transcription factor that is necessary for maturation of non-classical monocytes from classical monocytes. While Nr4a1 -/- mice are deficient in non-classical monocytes, results are confounded by macrophage hyper-activation. Nr4a1 se2/se2 mice lack a transcriptional activator, resulting in non-classical monocyte loss without macrophage hyper-activation., Main Body: We subjected Nr4a1 -/- and Nr4a1 se2/se2 mice to the laser-induced CNV model and performed multi-parameter flow cytometry. We found that both models lack non-classical monocytes, but only Nr4a1 -/- mice displayed increased CNV area. Additionally, CD11c + macrophages were increased in Nr4a1 -/- mice. Single-cell transcriptomic analysis uncovered that CD11c + macrophages were enriched from Nr4a1 -/- mice and expressed a pro-angiogenic transcriptomic profile that was disparate from prior reports of macrophage hyper-activation., Conclusions: These results suggest that non-classical monocytes are dispensable during CNV, and NR4A1 deficiency results in increased recruitment of pro-angiogenic macrophages., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Chronic wounds and scar formation are widespread due to limited suitable remedies. The macrophage is a crucial regulator in wound healing, controlling the onset and termination of inflammation and regulating other processes related to wound healing. The current breakthroughs in developing new medications and drug delivery methods have enabled the accurate targeting of macrophages in oncology and rheumatic disease therapies through clinical trials. These successes have cleared the way to utilize drugs targeting macrophages in various disorders. This review thus summarizes macrophage involvement in normal and pathologic wound healing. It further details the targets available for macrophage intervention and therapeutic strategies for targeting the behavior of macrophages in tissue repair and regeneration., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Mesenchymal migration usually happens on adhesive substrates, while cells adopt amoeboid migration on low/nonadhesive surfaces. Protein-repelling reagents, e.g., poly(ethylene) glycol (PEG), are routinely employed to resist cell adhering and migrating. Contrary to these perceptions, this work discovers a unique locomotion of macrophages on adhesive-nonadhesive alternate substrates in vitro that they can overcome nonadhesive PEG gaps to reach adhesive regions in the mesenchymal mode. Adhering to extracellular matrix regions is a prerequisite for macrophages to perform further locomotion on the PEG regions. Podosomes are found highly enriched on the PEG region in macrophages and support their migration across the nonadhesive regions. Increasing podosome density through myosin IIA inhibition facilitates cell motility on adhesive-nonadhesive alternate substrates. Moreover, a developed cellular Potts model reproduces this mesenchymal migration. These findings together uncover a new migratory behavior on adhesive-nonadhesive alternate substrates in macrophages., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose of Review: Recent technological advances have identified distinct subpopulations and roles of the cardiac innate immune cells, specifically macrophages and neutrophils. Studies on distinct metabolic pathways of macrophage and neutrophil in cardiac injury are expanding. Here, we elaborate on the roles of cardiac macrophages and neutrophils in concomitance with their metabolism in normal and diseased hearts., Recent Findings: Single-cell techniques combined with fate mapping have identified the clusters of innate immune cell subpopulations present in the resting and diseased hearts. We are beginning to know about the presence of cardiac resident macrophages and their functions. Resident macrophages perform cardiac homeostatic roles, whereas infiltrating neutrophils and macrophages contribute to tissue damage during cardiac injury with eventual role in repair. Prior studies show that metabolic pathways regulate the phenotypes of the macrophages and neutrophils during cardiac injury. Profiling the metabolism of the innate immune cells, especially of resident macrophages during chronic and acute cardiac diseases, can further the understanding of cardiac immunometabolism., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated. ATG5 is an essential autophagy protein that is required in innate immune cells to control neutrophil-dominated inflammation and promote survival during M. tuberculosis infection; however, the mechanistic basis for how ATG5 regulates neutrophil recruitment is unknown. To interrogate what innate immune cells require ATG5 to control neutrophil recruitment during M. tuberculosis infection, we used different mouse strains that conditionally delete Atg5 in specific cell types. We found that ATG5 is required in CD11c+ cells (lung macrophages and dendritic cells) to control the production of proinflammatory cytokines and chemokines during M. tuberculosis infection, which would otherwise promote neutrophil recruitment. This role for ATG5 is autophagy dependent, but independent of mitophagy, LC3-associated phagocytosis, and inflammasome activation, which are the most well-characterized ways that autophagy proteins regulate inflammation. In addition to the increased proinflammatory cytokine production from macrophages during M. tuberculosis infection, loss of ATG5 in innate immune cells also results in an early induction of TH17 responses. Despite prior published in vitro cell culture experiments supporting a role for autophagy in controlling M. tuberculosis replication in macrophages, the effects of autophagy on inflammatory responses occur without changes in M. tuberculosis burden in macrophages. These findings reveal new roles for autophagy proteins in lung resident macrophages and dendritic cells that are required to suppress inflammatory responses that are associated with poor control of M. tuberculosis infection., Competing Interests: The authors have declared that no competing interest exist., (Copyright: © 2023 Kinsella et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis-establishing stable spatial and functional relationships with specialized tissue cells-and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue. This ancillary cell type, which is developmentally and functionally distinct from haematopoietic stem cell and monocyte-derived macrophages, senses and integrates local and systemic information to provide specialized tissue cells with the growth factors, nutrient recycling and waste removal that are critical for tissue growth, homeostasis and repair. Resident macrophages contribute to organogenesis, promote tissue regeneration following damage and contribute to tissue metabolism and defence against infectious disease. A correlate is that genetic or environment-driven resident macrophage dysfunction is a cause of degenerative, metabolic and possibly inflammatory and tumoural diseases. In this Review, we aim to provide a conceptual outline of our current understanding of macrophage physiology and its importance in human diseases, which may inform and serve the design of future studies., (© 2023. Springer Nature Limited.)

Correct development and maturation of the enteric nervous system (ENS) is critical for survival 1 . At birth, the ENS is immature and requires considerable refinement to exert its functions in adulthood 2 . Here we demonstrate that resident macrophages of the muscularis externa (MMϕ) refine the ENS early in life by pruning synapses and phagocytosing enteric neurons. Depletion of MMϕ before weaning disrupts this process and results in abnormal intestinal transit. After weaning, MMϕ continue to interact closely with the ENS and acquire a neurosupportive phenotype. The latter is instructed by transforming growth factor-β produced by the ENS; depletion of the ENS and disruption of transforming growth factor-β signalling result in a decrease in neuron-associated MMϕ associated with loss of enteric neurons and altered intestinal transit. These findings introduce a new reciprocal cell-cell communication responsible for maintenance of the ENS and indicate that the ENS, similarly to the brain, is shaped and maintained by a dedicated population of resident macrophages that adapts its phenotype and transcriptome to the timely needs of the ENS niche., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Periodontal bone regeneration is a major challenge in the treatment of periodontitis. Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation, via conventional treatment. CD301b + macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment, but their role in periodontal bone repair has not been reported. The current study indicates that CD301b + macrophages may be a constituent component of periodontal bone repair, and that they are devoted to bone formation in the resolving phase of periodontitis. Transcriptome sequencing suggested that CD301b + macrophages could positively regulate osteogenesis-related processes. In vitro, CD301b + macrophages could be induced by interleukin 4 (IL-4) unless proinflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were present. Mechanistically, CD301b + macrophages promoted osteoblast differentiation via insulin-like growth factor 1 (IGF-1)/thymoma viral proto-oncogene 1 (Akt)/mammalian target of rapamycin (mTOR) signaling. An osteogenic inducible nano-capsule (OINC) consisting of a gold nanocage loaded with IL-4 as the "core" and mouse neutrophil membrane as the "shell" was designed. When injected into periodontal tissue, OINCs first absorbed proinflammatory cytokines in inflamed periodontal tissue, then released IL-4 controlled by far-red irradiation. These events collectively promoted CD301b + macrophage enrichment, which further boosted periodontal bone regeneration. The current study highlights the osteoinductive role of CD301b + macrophages, and suggests a CD301b + macrophage-targeted induction strategy based on biomimetic nano-capsules for improved therapeutic efficacy, which may also provide a potential therapeutic target and strategy for other inflammatory bone diseases., (© 2023. The Author(s).)

The recent revolution in tissue-resident macrophage biology has resulted largely from murine studies performed in C57BL/6 mice. Here, using both C57BL/6 and BALB/c mice, we analyze immune cells in the pleural cavity. Unlike C57BL/6 mice, naive tissue-resident large-cavity macrophages (LCMs) of BALB/c mice failed to fully implement the tissue-residency program. Following infection with a pleural-dwelling nematode, these pre-existing differences were accentuated with LCM expansion occurring in C57BL/6, but not in BALB/c mice. While infection drove monocyte recruitment in both strains, only in C57BL/6 mice were monocytes able to efficiently integrate into the resident pool. Monocyte-to-macrophage conversion required both T cells and interleukin-4 receptor alpha (IL-4Rα) signaling. The transition to tissue residency altered macrophage function, and GATA6 + tissue-resident macrophages were required for host resistance to nematode infection. Therefore, during tissue nematode infection, T helper 2 (Th2) cells control the differentiation pathway of resident macrophages, which determines infection outcome., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tissue-resident cardiac macrophage subsets mediate cardiac tissue inflammation and repair after acute myocardial infarction (AMI). CC chemokine receptor 2 (CCR2)-expressing macrophages have phenotypical similarities to M1-polarized macrophages, are pro-inflammatory, and recruit CCR2 + circulating monocytes to infarcted myocardium. Small extracellular vesicles (sEV) from CCR2 ̶ macrophages, which phenotypically resemble M2-polarized macrophages, promote anti-inflammatory activity and cardiac repair. Here, the authors harvested M2 macrophage-derived sEV (M2 EV ) from M2-polarized bone-marrow-derived macrophages for intramyocardial injection and recapitulation of sEV-mediated anti-inflammatory activity in ischemic-reperfusion (I/R) injured hearts. Rats and pigs received sham surgery; I/R without treatment; or I/R with autologous M2 EV treatment. M2 EV rescued cardiac function and attenuated injury markers, infarct size, and scar size. M2 EV inhibited CCR2 + macrophage numbers, reduced monocyte-derived CCR2 + macrophage recruitment to infarct sites, induced M1-to-M2 macrophage switching and promoted neovascularization. Analysis of M2 EV microRNA content revealed abundant miR-181b-5p, which regulated macrophage glucose uptake, glycolysis, and mitigated mitochondrial reactive oxygen species generation. Functional blockade of miR-181b-5p is detrimental to beneficial M2 EV actions and resulted in failure to inhibit CCR2 + macrophage numbers and infarct size. Taken together, this investigation showed that M2 EV rescued myocardial function, improved myocardial repair, and regulated CCR2 + macrophages via miR-181b-5p-dependent mechanisms, indicating an option for cell-free therapy for AMI., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Macro-autophagy is a highly conserved catabolic process among eukaryotes affecting macrophages. This work studies the genetic regulatory network involving the interplay between autophagy and macrophage polarization (activation). Autophagy-related genes (Atgs) and differentially expressed genes (DEGs) of macrophage polarization (M1-M2) were predicted, and their regulatory networks constructed. Naïve (M0) mouse bone marrow-derived monocytes were differentiated into M1 and M2a. Validation of the targets of Smad1, LC3A and LC3B, Atg16L1, Atg7, IL-6, CD68, Arg-1, and Vamp7 was performed in vitro. Immunophenotyping by flow cytometry revealed three macrophage phenotypes: M0 (IL-6 + /CD68 +), M1 (IL-6 + /CD68 + /Arg-1 +), and M2a (CD68 + /Arg-1). Confocal microscopy revealed increased autophagy in both M1 and M2a and a significant increase in the pre-autophagosomes size and number. Bafilomycin A increased the expression of CD68 and Arg-1 in all cell lineages. In conclusion, our approach predicted the protein targets mediating the interplay between autophagy and macrophage polarization. We suggest that autophagy reprograms macrophage polarization via CD68, arginase 1, Atg16L1-1, and Atg16L1-3. The current findings provide a foundation for the future use of macrophages in immunotherapy of different autoimmune disorders., (© 2022. The Author(s).)

Atherosclerosis is an inflammatory disease characterised by the formation of plaques, which are deposits of lipids and cholesterol-laden macrophages that form in the artery wall. The inflammation is often non-resolving, due in large part to changes in normal macrophage anti-inflammatory behaviour that are induced by the toxic plaque microenvironment. These changes include higher death rates, defective efferocytic uptake of dead cells, and reduced rates of emigration. We develop a free boundary multiphase model for early atherosclerotic plaques, and we use it to investigate the effects of impaired macrophage anti-inflammatory behaviour on plaque structure and growth. We find that high rates of cell death relative to efferocytic uptake results in a plaque populated mostly by dead cells. We also find that emigration can potentially slow or halt plaque growth by allowing material to exit the plaque, but this is contingent on the availability of live macrophage foam cells in the deep plaque. Finally, we introduce an additional bead species to model macrophage tagging via microspheres, and we use the extended model to explore how high rates of cell death and low rates of efferocytosis and emigration prevent the clearance of macrophages from the plaque., (© 2023. The Author(s).)

The adult mammalian heart has limited regenerative capacity, while the neonatal heart fully regenerates during the first week of life. Postnatal regeneration is mainly driven by proliferation of preexisting cardiomyocytes and supported by proregenerative macrophages and angiogenesis. Although the process of regeneration has been well studied in the neonatal mouse, the molecular mechanisms that define the switch between regenerative and nonregenerative cardiomyocytes are not well understood. Here, using in vivo and in vitro approaches, we identified the lncRNA Malat1 as a key player in postnatal cardiac regeneration. Malat1 deletion prevented heart regeneration in mice after myocardial infarction on postnatal day 3 associated with a decline in cardiomyocyte proliferation and reparative angiogenesis. Interestingly, Malat1 deficiency increased cardiomyocyte binucleation even in the absence of cardiac injury. Cardiomyocyte-specific deletion of Malat1 was sufficient to block regeneration, supporting a critical role of Malat1 in regulating cardiomyocyte proliferation and binucleation, a landmark of mature nonregenerative cardiomyocytes. In vitro, Malat1 deficiency induced binucleation and the expression of a maturation gene program. Finally, the loss of hnRNP U, an interaction partner of Malat1, induced similar features in vitro, suggesting that Malat1 regulates cardiomyocyte proliferation and binucleation by hnRNP U to control the regenerative window in the heart.

Fluorescent nanodiamonds (FNDs) with negative nitrogen-vacancy (NV - ) defect centers are great probes for biosensing applications, with potential to act as biomarkers for cell differentiation. To explore this concept, uptake of FNDs (≈120 nm) by THP-1 monocytes and monocyte-derived M0-macrophages is studied. The time course analysis of FND uptake by monocytes confirms differing FND-cell interactions and a positive time-dependence. No effect on cell viability, proliferation, and differentiation potential into macrophages is observed, while cells saturated with FNDs, unload the FNDs completely by 25 cell divisions and subsequently take up a second dose effectively. FND uptake variations by THP-1 cells at early exposure-times indicate differing phagocytic capability. The cell fraction that exhibits relatively enhanced FND uptake is associated to a macrophage phenotype which derives from spontaneous monocyte differentiation. In accordance, chemical-differentiation of the THP-1 cells into M0-macrophages triggers increased and homogeneous FND uptake, depleting the fraction of cells that were non-responsive to FNDs. These observations imply that FND uptake allows for distinction between the two cell subtypes based on phagocytic capacity. Overall, FNDs demonstrate effective cell labeling of monocytes and macrophages, and are promising candidates for sensing biological processes that involve cell differentiation., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

In Mycobacterium avium infections, macrophages play a critical role in the host defense response. Apoptosis inhibitor of macrophage (AIM), also known as CD5L, may represent a novel supportive therapy against various diseases, including metabolic syndrome and infectious diseases. The mechanisms of AIM include modulating lipid metabolism in macrophages and other host cells. We investigated the role of AIM in M. avium infections in vitro and in vivo. In a mouse model of M. avium pneumonia, foamy macrophages were induced 6 wk after infection. The bacteria localized in these macrophages. Flow cytometric analysis also confirmed that the percentage of CD11chighMHCclassIIhigh interstitial and alveolar macrophages, a cell surface marker defined as foamy macrophages, increased significantly after infection. AIM in alveolar lavage fluid and serum gradually increased after infection. Administration of recombinant AIM significantly increased the number of bacteria in the lungs of mice, accompanied by the induction of inflammatory cytokine and iNOS expression. In mouse bone marrow-derived macrophages, the mRNA expression of AIM after M. avium infection and the amount of AIM in the supernatant increased prior to the increase in intracellular bacteria. Infected cells treated with anti-AIM Abs had fewer bacteria and a higher percentage of apoptosis-positive cells than infected cells treated with isotype control Abs. Finally, AIM in the sera of patients with M. avium-pulmonary disease was measured and was significantly higher than in healthy volunteers. This suggests that AIM production is enhanced in M. avium-infected macrophages, increasing macrophage resistance to apoptosis and providing a possible site for bacterial growth., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Sensory neurons located in dorsal root ganglia (DRG) convey sensory information from peripheral tissue to the brain. After peripheral nerve injury, sensory neurons switch to a regenerative state to enable axon regeneration and functional recovery. This process is not cell autonomous and requires glial and immune cells. Macrophages in the DRG (DRGMacs) accumulate in response to nerve injury, but their origin and function remain unclear. Here, we mapped the fate and response of DRGMacs to nerve injury using macrophage depletion, fate-mapping, and single-cell transcriptomics. We identified three subtypes of DRGMacs after nerve injury in addition to a small population of circulating bone-marrow-derived precursors. Self-renewing macrophages, which proliferate from local resident macrophages, represent the largest population of DRGMacs. The other two subtypes include microglia-like cells and macrophage-like satellite glial cells (SGCs) (Imoonglia). We show that self-renewing DRGMacs contribute to promote axon regeneration. Using single-cell transcriptomics data and CellChat to simulate intercellular communication, we reveal that macrophages express the neuroprotective and glioprotective ligand prosaposin and communicate with SGCs via the prosaposin receptor GPR37L1. These data highlight that DRGMacs have the capacity to self-renew, similarly to microglia in the Central nervous system (CNS) and contribute to promote axon regeneration. These data also reveal the heterogeneity of DRGMacs and their potential neuro- and glioprotective roles, which may inform future therapeutic approaches to treat nerve injury.

Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD-treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and antiinflammatory pathways, including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure to lipids from the HFD prevented tethering and uptake of apoptotic cells and Il10 induction. Milk fat globule-EGF factor 8 (MFGE8) is a bridging molecule that facilitates macrophage uptake of dead cells. MFGE8 also facilitates lipid uptake, and we demonstrate that dietary lipids interfere with MFGE8-mediated macrophage apoptotic neutrophil uptake and subsequent Il10 production. Our findings demonstrate that HFD promotes intestinal pathology by interfering with macrophage clearance of dead neutrophils, leading to unresolved tissue damage.

N6-methyladenosine (m 6 A) is one of the most prevalent internal transcriptional modifications. Evidence has highlighted changes in m 6 A in metabolic disorders and various metabolic diseases. However, the precise mechanisms of these m 6 A changes in such conditions are not understood. Macrophages are crucial for the innate immune system and exert either beneficial or harmful roles in metabolic disease. Notably, m 6 A was found to be closely related to macrophage phenotype and dysfunction. In this review, we summarize m 6 A in macrophage function from the perspective of macrophage development, activation, and polarization, pyroptosis, and metabolic disorders. Furthermore, we discuss how m 6 A-mediated macrophage function affects metabolic diseases, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD). Finally, we discuss challenges and prospects for m 6 A in macrophage and metabolic diseases with the aim of providing guidance for the treatment of metabolic diseases., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

As the brain is a prime immune privileged organ, immune responses in it were not studied as intensively as other peripheral organs in the past. However, the brain is studded with immune cells called microglia, which play important roles particularly in diseased conditions. In addition, from recent descriptive works, we have learned a lot about immune cells in neighboring tissues. Recent progress has rather made it clearer that the immune responses in and around the brain are complicated reactions with both positive and negative effects. And we still have not identified the way(s) we should pursue for clinical applications. Here we introduce microglia and macrophages in the steady state. We also discuss their roles in stroke, a major cause of death and disability in Japan, and Alzheimer's disease, which account for 60 to 70% of dementia.

(1) Background: the miR-301a is well known involving the proliferation and migration of tumor cells. However, the role of miR-301a in the migration and phagocytosis of macrophages is still unclear. (2) Methods: sciatic nerve injury, liver injury models, as well as primary macrophage cultures were prepared from the miR-301a knockout (KO) and wild type (WT) mice to assess the macrophage's migration and phagocytosis capabilities. Targetscan database analysis, Western blotting, siRNA transfection, and CXCR4 inhibition or activation were performed to reveal miR301a's potential mechanism. (3) Results: the macrophage's migration and phagocytosis were significantly attenuated by the miR-301a KO both in vivo and in vitro. MiR-301a can target Yin-Yang 1 (YY1), and miR-301a KO resulted in YY1 up-regulation and CXCR4 (YY1's down-stream molecule) down-regulation. siYY1 increased the expression of CXCR4 and enhanced migration and phagocytosis in KO macrophages. Meanwhile, a CXCR4 inhibitor or agonist could attenuate or accelerate, respectively, the macrophage migration and phagocytosis. (4) Conclusions: current findings indicated that miR-301a plays important roles in a macrophage's capabilities of migration and phagocytosis through the YY1/CXCR4 pathway. Hence, miR-301a might be a promising therapeutic candidate for inflammatory diseases by adjusting macrophage bio-functions.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, which is mainly characterized by lipid deposition and inflammatory response. Macrophages (MΦ), as the key mediators of the inflammatory response, run through all stages of the occurrence and development of AS, from plaque initiation to the transition to vulnerable plaques, and are regarded as important therapeutic targets. It was previously thought that the atherogenic mechanism of MΦ was mainly due to their phagocytosis of lipids, resulting in excessive foam cells aggregated on the arterial wall. However, increasing evidence has revealed the diversity of AS mechanisms caused by MΦ. For example, MΦ present a continuum phenotypic spectrum, and their polarization has been demonstrated to play a vital role in the regulation of AS-related inflammatory response. MΦ apoptosis and the ability of MΦ to clean up apoptotic cells (also known as efferocytosis) are crucial determinants of AS lesion progression and plaque stability. Hence, this review probes into the contradictory regulation of MΦ on AS based on polarization, apoptosis, and efferocytosis, designed to highlight the complex and interrelated regulated network of MΦ promoting AS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Atherosclerosis is an inflammatory disease depending on the buildup, called plaque, of lipoproteins, cholesterol, extracellular matrix elements, and various types of immune and non-immune cells on the artery walls. Plaque development and growth lead to the narrowing of the blood vessel lumen, blocking blood flow, and eventually may lead to plaque burst and a blood clot. The prominent cellular components of atherosclerotic plaque are the foam cells, which, by trying to remove lipoprotein and cholesterol surplus, also participate in plaque development and rupture. Although the common knowledge is that the foam cells derive from macrophages, studies of the last decade clearly showed that macrophages are not the only cells able to form foam cells in atherosclerotic plaque. These findings give a new perspective on atherosclerotic plaque formation and composition and define new targets for anti-foam cell therapies for atherosclerosis prevention. This review gives a concise description of foam cells of different pedigrees and describes the main mechanisms participating in their formation and function.

Skeletal muscle injury in aged rodents is characterized by an asynchronous infiltration of pro- and anti-inflammatory macrophage waves, leading to improper and incomplete regeneration. It is unclear whether this aberration also occurs in aged human muscle. In this study, we quantified the macrophage responses in a human model of muscle damage and regeneration induced by electrical stimulation in 7 young and 21 older adults. At baseline, total resident macrophage (CD68 + /DAPI + ) content was not different between young and old subjects, but pro-inflammatory (CD206 - /CD68 + /DAPI + ) macrophage content was lower in the old. Following damage, muscle Infiltration of CD206 - /CD68 + /DAPI + macrophages was lower in old relative to young subjects. Further, only the increase in CD206 - /CD68 + macrophages correlated with the change in muscle satellite cell content. Our data show that older individuals have a compromised macrophage response during muscle regeneration, pointing to an altered inflammatory response as a potential mechanism for reduced muscle regenerative efficacy in aged humans., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)