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CD163, a scavenger receptor with anti-inflammatory function expressed exclusively on monocytes/macrophages, is dysregulated in cases of diabetes complications. This study aimed to characterize circulating CD163+ monocytes in the presence (D+Comps) or absence (D−Comps) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D+Comps or D−Comps. Out of 10,868 differentially expressed genes identified between D+Comps and D−Comps, 885 were up-regulated and 190 were down-regulated with a ≥ 1.5-fold change. In D+Comps, 'regulation of centrosome cycle' genes were enriched 6.7-fold compared to the reference genome. MIR27A, MIR3648-1, and MIR23A, the most up-regulated and CD200R1, the most down-regulated gene, were detected in D+Comps from the list of 75 'genes of interest'. CD163+ monocytes in D+Comps had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD86. A gene–protein network identified down-regulated TLR4 and CD11b as 'hub-nodes'. In conclusion, this study reports novel insights into CD163+ monocyte dysregulation in diabetes-related complications. Enriched centrosome cycle genes and up-regulated miRNAs linked to apoptosis, coupled with down-regulated monocyte activation, recruitment, and immune regulation, suggest functionally distinct CD163+ monocytes in cases of diabetes complications. Further investigation is needed to confirm their role in diabetes-related tissue damage. [ABSTRACT FROM AUTHOR]

Glycoprotein non‐metastatic melanoma protein B (GPNMB) is up‐regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid‐beta (Aβ) peptides. However, whether the microglial GPNMB can recognize the fibrous Aβ peptides as ligands remains unknown. In this study, we report that the truncated form of GPNMB, the antigen for 9F5, serves as a scavenger receptor for oligomeric Aβ1‐42 (o‐Aβ1‐42) in rat primary type 1 MG. 125I‐labeled o‐Aβ1‐42 exhibited specific and saturable endosomal/lysosomal degradation in primary‐cultured type 1 MG from GPNMB‐expressing wild‐type mice, whereas the degradation activity was markedly reduced in cells from Gpnmb‐knockout mice. The Gpnmb‐siRNA significantly inhibits the degradation of 125I‐o‐Aβ1‐42 by murine microglial MG5 cells. Therefore, GPNMB contributes to mouse MG's o‐Aβ1‐42 clearance. In rat primary type 1 MG, the cell surface expression of truncated GPNMB was confirmed by a flow cytometric analysis using a previously established 9F5 antibody. 125I‐labeled o‐Aβ1‐42 underwent endosomal/lysosomal degradation by rat primary type 1 MG in a dose‐dependent fashion, while the 9F5 antibody inhibited the degradation. The binding of 125I‐o‐Aβ1‐42 to the rat primary type 1 MG was inhibited by 42% by excess unlabeled o‐Aβ1‐42, and by 52% by the 9F5 antibody. Interestingly, the 125I‐o‐Aβ1‐42 degradations by MG‐like cells from human‐induced pluripotent stem cells was inhibited by the 9F5 antibody, suggesting that truncated GPNMB also serve as a scavenger receptor for o‐Aβ1‐42 in human MG. Our study demonstrates that the truncated GPNMB (the antigen for 9F5) binds to oligomeric form of Aβ1‐42 and functions as a scavenger receptor on MG, and 9F5 antibody can act as a blocking antibody for the truncated GPNMB. [ABSTRACT FROM AUTHOR]

Copyright of Current Biotechnology (2095-2341) is the property of Chinese Academy of Agricultural Sciences, Institute of Biotechnology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Medical Journal of Babylon is the property of Wolters Kluwer India Pvt Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

SCARF1 (scavenger receptor class F member 1, SREC-1 or SR-F1) is a type I transmembrane protein that recognizes multiple endogenous and exogenous ligands such as modified low-density lipoproteins (LDLs) and is important for maintaining homeostasis and immunity. But the structural information and the mechanisms of ligand recognition of SCARF1 are largely unavailable. Here, we solve the crystal structures of the N-terminal fragments of human SCARF1, which show that SCARF1 forms homodimers and its epidermal growth factor (EGF)-like domains adopt a long-curved conformation. Then, we examine the interactions of SCARF1 with lipoproteins and are able to identify a region on SCARF1 for recognizing modified LDLs. The mutagenesis data show that the positively charged residues in the region are crucial for the interaction of SCARF1 with modified LDLs, which is confirmed by making chimeric molecules of SCARF1 and SCARF2. In addition, teichoic acids, a cell wall polymer expressed on the surface of gram-positive bacteria, are able to inhibit the interactions of modified LDLs with SCARF1, suggesting the ligand binding sites of SCARF1 might be shared for some of its scavenging targets. Overall, these results provide mechanistic insights into SCARF1 and its interactions with the ligands, which are important for understanding its physiological roles in homeostasis and the related diseases.

Lipid distribution in an organism is mediated by the interplay between lipoprotein particles, lipoprotein receptors and class B scavenger receptors of the CD36 family. CD36 is a multifunctional protein mediating lipid uptake, mobilization and signaling at the plasma membrane and inside of the cell. The CD36 protein family has 14 members in Drosophila melanogaster, which allows for the differentiated analysis of their functions. Here, we unravel a role for the so far uncharacterized scavenger receptor Bez in lipid export from Drosophila adipocytes. Bez shares the lipid binding residue with CD36 and is expressed at the plasma membrane of the embryonic, larval and adult fat body. Bez loss of function lowers the organismal availability of storage lipids and blocks the maturation of egg chambers in ovaries. We demonstrate that Bez interacts with the APOB homolog Lipophorin at the plasma membrane of adipocytes and trace the Bez-dependent transfer of an alkyne-labeled fatty acid from adipocytes to Lipophorin. Our study demonstrates how lipids are distributed by scavenger receptor-lipoprotein interplay and contribute to the metabolic control of development. [ABSTRACT FROM AUTHOR]

Scavenger receptors are a protein superfamily that typically consists of one or more repeats of the scavenger receptor cysteine-rich structural domain (SRCRD), which is an ancient and highly conserved protein module. The expression and purification of eukaryotic proteins containing multiple disulfide bonds has always been challenging. The expression systems that are commonly used to express SRCRD proteins mainly consist of eukaryotic protein expression systems. Herein, we established a high-level expression strategy of a Type B SRCRD unit from human salivary agglutinin using the Escherichia coli expression system, followed by a refolding and purification process. The untagged recombinant SRCRD was expressed in E. coli using the pET-32a vector, which was followed by a refolding process using the GSH/GSSG redox system. The SRCRD expressed in E. coli SHuffle T7 showed better solubility after refolding than that expressed in E. coli BL21(DE3), suggesting the importance of the disulfide bond content prior to refolding. The quality of the refolded protein was finally assessed using crystallization and crystal structure analysis. As proteins refolded from inclusion bodies exhibit a high crystal quality and reproducibility, this method is considered a reliable strategy for SRCRD protein expression and purification. To further confirm the structural integrity of the refolded SRCRD protein, the purified protein was subjected to crystallization using sitting-drop vapor diffusion method. The obtained crystals of SRCRD diffracted X-rays to a resolution of 1.47 Å. The solved crystal structure appeared to be highly conserved, with four disulfide bonds appropriately formed. The surface charge distribution of homologous SRCRD proteins indicates that the negatively charged region at the surface is associated with their calcium-dependent ligand recognition. These results suggest that a high-quality SRCRD protein expressed by E. coli SHuffle T7 can be successfully folded and purified, providing new options for the expression of members of the scavenger receptor superfamily. [ABSTRACT FROM AUTHOR]

Scavenger receptors participate in a wide range of biological functions after binding to multiple non‐self or altered self‐ligands. Among them, CD5 and CD6 are lymphocyte scavenger receptors known to interact with different microbial‐associated molecular patterns, and the administration of the recombinant soluble ectodomains of human CD5 (rshCD5) and/or CD6 (rshCD6) has shown therapeutic/prophylactic potential in experimental models of fungal, bacterial and echinococcal infections. The latter is a zoonosis caused by the larval stage of the cestode parasite Echinococcus granulosus sensu lato, which in humans can induce secondary cystic echinococcosis (CE) after the spillage of protoscoleces contained within fertile cysts, either spontaneously or during surgical removal of primary hydatid cysts. Herein, we have analysed the mechanisms behind the significant protection observed in the mouse model of secondary CE following prophylactic administration of rshCD5 or rshCD6. Our results show that both molecules exhibit intrinsic antiparasitic activities in vitro, as well as immunomodulatory functions during early secondary CE, mainly through Th1/Th17 cytokine bias and promotion of peritoneal polyreactive antibodies. These data support the relevance of the parasite components bound by rshCD5 and rshCD6, as well as the potential of their prophylactic administration as a useful strategy to reduce secondary CE in patients. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results in a large amount of tissue cell debris in the lesion site, which interacts with various cytokines, including inflammatory factors, and the intrinsic glial environment of the central nervous system(CNS) to forman inhibitory microenvironment that impedes nerve regeneration. The efficient clearance of tissue debris is crucial for the resolution of the inhibitory microenvironment after SCI. Macrophages are themain cells responsible for tissue debris removal after SCI. However, the high lipid content in tissue debris and the dysregulation of lipid metabolism within macrophages lead to their transformation into foamy macrophages during the phagocytic process. This phenotypic shift is associated with a further pro-inflammatory polarization that may aggravate neurological deterioration and hamper nerve repair. In this review, we summarize the phenotype and metabolism of macrophages under inflammatory conditions, as well as the mechanisms and consequences of foam cell formation after SCI. Moreover, we discuss two strategies for foamcell modulation and several potential therapeutic targets that may enhance the treatment of SCI. [ABSTRACT FROM AUTHOR]

Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE −/ −‐ mice on a HFD. We subsequently injected mice with AAV- KLF15 and AAV- LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis. [Display omitted] • KLF15 expression in macrophages was downregulated during atherosclerosis. • The progression of atherosclerosis was attenuated by KLF15 overexpression. • KLF15 overexpression prevented increased macrophage lipid deposition and foam cell formation. • Downregulation of KLF15 expression promoted macrophage foam cell formation. • Macrophage KLF15 transcriptionally downregulated OLR-1 expression by binding to its promoter. [ABSTRACT FROM AUTHOR]

Jianjun Jiang, Yang Liu Department of General Surgery, Vascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Yang Liu, Department of General Surgery, Vascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China, Tel +86 18560088317, Email liuyang_sdu@126.comBackground: A comprehensive study of the distribution and role of immune/inflammatory cells in thrombosis is still lacking because traditional pathology techniques cannot accomplish the analysis of numerous protein and genetic data simultaneously. We aimed to evaluate the feasibility of digital spatial profiling (DSP) to study immune/inflammation reaction in thrombosis progression.Methods and Results: An 82-year-old male patient underwent iliofemoral thrombectomy at our institution. The white, mixed and red thrombi were fixed in formalin, dehydrated in ethanol and embedded in paraffin, which were incubated with morphology-labeled fluorescent antibodies (CD45, SYTO13) and the entire target mixture in GeoMx Whole Transcriptome Atlas panel. DSP system was applied to investigate the regions of interest from fluorescence imaging. Fluorescence imaging showed infiltration of immune/inflammation cells in white, mixed and red thrombosis. Whole genome sequencing revealed 16 genes differentially expressed. Pathway enrichment analysis revealed that these genes were significantly enriched in ligand binding and uptake related signaling pathways of the scavenger receptor. The distribution of immune/inflammation cell subsets was different in white, mixed and red thrombosis. The abundance of endothelial cells, CD8 naive T cells, and macrophages in red thrombosis was significantly higher than in mixed and white thrombosis.Conclusion: The results showed that DSP can facilitate efficient analysis using very few thrombosis samples and provide valuable new leads, suggesting that DSP may be a viable and important new tool to study thrombosis and inflammation.Keywords: digital spatial profiling, immune/inflammation cell, arterial thrombosis, whole genome sequencing, scavenger receptor

Macrophage‐derived foam cell formation is critical for the initiation and development of atherosclerosis, which contributes to atherosclerotic cardiovascular disease (ASCVD). Glutathione peroxidase 4 (GPX4), a crucial ferroptosis regulator, protects cells from excessive oxidative stress by neutralizing lipid peroxidation. However, the role of macrophage GPX4 in foam cell formation remains unknown. We reported that oxidized low‐density lipoprotein (oxLDL) upregulated GPX4 expression in macrophages. Using the Cre‐loxP system, we generated myeloid cell‐specific Gpx4 knockout (Gpx4myel‐KO) mice. Bone marrow‐derived macrophages (BMDMs) were isolated from WT and Gpx4myel‐KO mice and incubated with modified low‐density lipoprotein (LDL). We found that Gpx4 deficiency promoted foam cell formation and increased the internalization of modified LDL. Mechanistic studies unveiled that Gpx4 knockout upregulated scavenger receptor type A and LOX‐1 expression and downregulated ABCA1 and ABCG1 expression. Collectively, our study lends a novel insight into the role of GPX4 in suppressing macrophage‐derived foam cell formation and suggests GPX4 as a promising therapeutic target to interfere with atherosclerosis‐related diseases. [ABSTRACT FROM AUTHOR]

As the final step in apoptosis, apoptotic cells (ACs) are swiftly removed by specialized phagocytes, such as macrophages, or nonprofessional phagocytes, such as epidermal cells. Genetic studies of model organisms such as Caenorhabditis elegans have helped to elucidate the mechanisms of AC clearance and the underlying causes of disorders related to the dysregulation of these pathways. C. elegans possesses six class B scavenger receptor homologs, but whether they affect apoptosis is unknown. Here, we show that only the loss of function of scav‐3, the C. elegans homolog of human lysosomal integral membrane protein‐2, resulted in a considerable accumulation of cell corpses, which was caused by a failure in degradation rather than engulfment. SCAV‐3 was found to be widely distributed and localized in lysosomes to maintain the integrity of the lysosomal membrane. Further study revealed that loss of scav‐3 had no effect on phagosome maturation or the recruitment of lysosomes to phagosomes carrying cell corpses. Moreover, we discovered that the hydrolytic enzymes contained in the lysosomes were reduced in phagosomes in scav‐3 mutants. Thus, hydrolases may leak from the damaged lysosome during phagolysosome formation due to the loss of scav‐3 function, which reduces lysosome digestion activity and thus directly contributes to the elimination of ACs.

【Objective】The resistance of Plutella xylostella to chemical insecticides is increasing year by year, which makes RNAi (RNA interference) pesticides widely concerned. The P. xylostella SR have phagocytic and pathogenclearing abilities in cellular immunity, rendering them a promising target for RNAi pesticides. This study explores alternative targets for such pesticides by investigating the SR gene family in P. xylostella.【Method】Based on the P. xylostella genome, we comprehensively analyzed the physicochemical properties, transmembrane structure, phylogenetic evolution, secondary and tertiary structure prediction, conserved protein motifs and phosphorylation site prediction of SR gene family.【Result】The SR gene family of P. xylostella has 12 CD36 protein sequences with similar physicochemical properties and functional structures, all of which contain multiple hydrophilic and hydrophobic regions as well as two transmembrane helical regions. Their secondary and tertiary structures feature irregular coiling with the highest serine content in the phosphorylation site. A total of six species, including P. xylostella, Bombyx mori, Anopheles gambiae, Drosophila melanogaster, Manduca sexta and Tribolium castaneum contained 117 CD36 protein sequences that were classified into five distinct branches on the evolutionary tree. Genes with similar structures were grouped together within the same branch, indicating a high conservation throughout evolution. CD36px4 and CD36px5 exhibit more intricate tertiary structures. The motif 19 and motif 20 are exclusive to CD36px4, suggesting their potential involvement in species evolution. With a staggering 143 phosphorylation sites, CD36px4 may play a crucial role in the phagocytosis and clearance of apoptotic cells.【Conclusion】The 12 SRs identified are transmembrane proteins with abundant phosphorylation sites, predicted to participate in various physiological processes such as intracellular and extracellular material transport, signal transduction, energy metabolism, and apoptosis regulation. They also possess the functions of mediating phagocytosis and clearance of cellular debris. These receptors represent a promising target for RNAi-based pesticides. The results have provided a crucial foundation for the screening of RNAi pesticide targets.

The specific recognition of serum proteins by scavenger receptors is critical and fundamental in many biological processes. However, the underlying mechanism of scavenger receptor‐serum protein interaction remains elusive. In this work, taking scavenger receptors class A1 (SR‐A1) as an example, we systematically investigate its interaction with human serum albumin (HSA) at different states through a combination of molecular docking and all‐atom molecular dynamics simulations. It is found that native HSA can moderately bind to collagen‐like (CL) region or scavenger receptor cysteine‐rich (SRCR) region, with both electrostatic (ELE) and van der Waals (VDW) interactions, playing important roles. After maleylation, the binding energy, particularly the ELE energy, between HSA and CL region is significantly enhanced, while the binding energy between HSA and SRCR region remains nearly unchanged. Additionally, we also observe that unfolding of the secondary structures in HSA leads to a larger contact surface area between denatured HSA and CL region, but has little impact on the HSA‐SRCR region interaction. Therefore, similar to maleylated HSA, denatured HSA is also more likely to bind to the CL region of SR‐A1. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis (CF) airway disease is characterized by chronic inflammation, featuring neutrophil influx to the lumen. Airway macrophages (AMs) can promote both inflammation and resolution, and are thus critical to maintaining and restoring homeostasis. CF AM functions, specifically scavenging activity and resolution of inflammation, have been shown to be impaired, yet underlying processes remain unknown. We hypothesized that impaired CF AM function results from an altered expression of receptors that mediate or regulate scavenging, and set out to investigate changes in expression of these markers during the early stages of CF lung disease. Methods: Bronchoalveolar lavage fluid (BALF) was collected from 50 children with CF aged 1, 3 or 5 years. BALF cells were analyzed using flow cytometry. Expression levels of surface markers on AMs were expressed as median fluorescence intensities (MFI) or percentage of AMs positive for these markers. The effect of age and neutrophilic inflammation, among other variables, on marker expression was assessed with a multivariate linear regression model. Results: AM expression of scavenger receptor CD163 decreased with age (p = 0.016) and was negatively correlated with BALF %neutrophils (r = -0.34, p = 0.016). AM expression of immune checkpoint molecule SIRPa also decreased with age (p = 0.0006), but did not correlate with BALF %neutrophils. Percentage of AMs expressing lipid scavenger CD36 was low overall (mean 20.1% ± 16.5) and did not correlate with other factors. Conversely, expression of immune checkpoint PD-1 was observed on the majority of AMs (mean PD-1pos 72.9% ± 11.8), but it, too, was not affected by age or BALF %neutrophils. Compared to matched blood monocytes, AMs had a higher expression of CD16, CD91, and PD-1, and a lower expression of CD163, SIRPa and CD36. Conclusion: In BALF of preschool children with CF, higher age and/or increased neutrophilic inflammation coincided with decreased expression of scavenger receptors on AMs. Expression of scavenging receptors and regulators showed a distinctly different pattern in AMs compared to blood monocytes. These findings suggest AM capacity to counter inflammation and promote homeostasis reduces during initiation of CF airway disease and highlight new avenues of investigation into impaired CF AM function. [ABSTRACT FROM AUTHOR]

The immune deficiency (IMD) pathway is critical for elevating host immunity in both insects and crustaceans. The IMD pathway activation in insects is mediated by peptidoglycan recognition proteins, which do not exist in crustaceans, suggesting a previously unidentified mechanism involved in crustacean IMD pathway activation. In this study, we identified a Marsupenaeus japonicus B class type III scavenger receptor, SRB2, as a receptor for activation of the IMD pathway. SRB2 is up-regulated upon bacterial challenge, while its depletion exacerbates bacterial proliferation and shrimp mortality via abolishing the expression of antimicrobial peptides. The extracellular domain of SRB2 recognizes bacterial lipopolysaccharide (LPS), while its C-terminal intracellular region containing a cryptic RHIM-like motif interacts with IMD, and activates the pathway by promoting nuclear translocation of RELISH. Overexpressing shrimp SRB2 in Drosophila melanogaster S2 cells potentiates LPS-induced IMD pathway activation and diptericin expression. These results unveil a previously unrecognized SRB2-IMD axis responsible for antimicrobial peptide induction and restriction of bacterial infection in crustaceans and provide evidence of biological diversity of IMD signaling in animals. A better understanding of the innate immunity of crustaceans will permit the optimization of prevention and treatment strategies against the arising shrimp diseases. [ABSTRACT FROM AUTHOR]

Experimental toxoplasmosis is an excellent model for adaptive immune response. Gamma-irradiated tachyzoites or soluble tachyzoite antigen extracts (STag) induce protection against experimental toxoplasmosis in mice. Scavenger receptors recognize irradiated proteins, promote their entry into cells, and lead to antigen presentation. CD36 is a specific scavenger receptor involved in intracellular transport of free fatty acid (FFA), cellular recycling, and intracellular trafficking in lipid rafts outside the lysosomal pathways. CD36 is also associated with an altered immune response, as CD36−/− mice presented some immune defects in the cyst-forming Toxoplasma gondii. We studied T. gondii infection in CD36−/− mice, naïve or immunized, with irradiated T. gondii STags by investigating protection, antibody production, and primed macrophage transplantation. CD36−/− mice presented no resistance against the viable RH tachyzoites, even after immunization with gamma-irradiated STags that protected wild-type mice. The animals presented poor humoral responses to both immunogens despite adequate levels of serum immunoglobulins. CD36−/− mice failed to induce protection against virulent T. gondii infection with inadequate antibody production or an innate response. Irradiated antigens failed to induce antibodies in CD36−/− mice and only produced adequate levels of immunoglobulin G when transplanted with irradiated STag-primed wild-type macrophages. The CD36 pathway is necessary for humoral response against the irradiated antigen; however, several other pathways are also involved in mounting a humoral response against any antigen. CD36 is a multipurpose molecule for FFA and lipid transport, as well as for the immune response, and gamma radiation mimics the innate response by targeting irradiated antigens of this pathway. [ABSTRACT FROM AUTHOR]

Lipid metabolism is an important metabolic process of the body, and its disorder will lead to many diseases. Cluster of differentiation 36 (CD36) is a scavenger receptor highly expressed in monocytes, macrophages, smooth muscle cells and adipocytes. It is the main receptor and transporter for the recognition of oxidized low-density lipoprotein or long-chain fatty acids. So it plays an important role in the process of lipid metabolism. The review recapitulates the update and current advances on the structure and function of CD36 gene and protein, expounds the role of CD36 in the process of lipid metabolism, and systematically summarizes the molecular mechanism that CD36 cascade AMPK, mTOR and MAPK signaling pathways to participate in the process of lipid metabolism, providing a theoretical basis for the relevant biological research. [ABSTRACT FROM AUTHOR]

The acquisition of distinct branch sizes and shapes is a central aspect in tubular organ morphogenesis and function. In the Drosophila airway tree, the interplay of apical extracellular matrix (ECM) components with the underlying membrane and cytoskeleton controls tube elongation, but the link between ECM composition with apical membrane morphogenesis and tube size regulation is elusive. Here, we characterized Emp (epithelial membrane protein), a Drosophila CD36 homolog belonging to the scavenger receptor class B protein family. emp mutant embryos fail to internalize the luminal chitin deacetylases Serp and Verm at the final stages of airway maturation and die at hatching with liquid filled airways. Emp localizes in apical epithelial membranes and shows cargo selectivity for LDLr-domain containing proteins. emp mutants also display over elongated tracheal tubes with increased levels of the apical proteins Crb, DE-cad, and phosphorylated Src (p-Src). We show that Emp associates with and organizes the βH-Spectrin cytoskeleton and is itself confined by apical F-actin bundles. Overexpression or loss of its cargo protein Serp lead to abnormal apical accumulations of Emp and perturbations in p-Src levels. We propose that during morphogenesis, Emp senses and responds to luminal cargo levels by initiating apical membrane endocytosis along the longitudinal tube axis and thereby restricts airway elongation.

This study aimed to compare tissue levels of CD80 (pro-inflammatory macrophage-related surface marker), CD163, and CD206 (anti-inflammatory macrophage-related surface markers), and their ratios in periodontal and peri-implant health and disease. Altogether, 36 tissue samples were obtained from 36 participants with clinically healthy gingiva (n = 10), healthy peri-implant mucosa (n = 8), periodontitis lesions (n = 9), and peri-implantitis lesions (n = 9). CD80, CD163, and CD206 levels were assessed with immunoblotting. CD163 levels were found to be decreased (p = 0.004), and the CD80/CD163 ratio was found to be elevated (p = 0.002) in periodontitis lesions compared to healthy gingiva. Peri-implantitis lesions showed a tendency towards a higher CD80/CD163 ratio than in healthy peri-implant mucosa with a borderline difference (p = 0.054). No statistically significant difference was detected in CD80, CD163, and CD206 levels of periodontitis lesions when compared to peri-implantitis, and in healthy gingiva when compared to healthy peri-implant mucosa. A disruption in CD80/CD163 balance seems to be related to the pathogenesis of periodontitis and peri-implantitis, being less prominent in the latter. The reason behind this phenomenon may be either suppressed CD163 expression or reduced CD163+ anti-inflammatory macrophage abundance.

As the final step in apoptosis, apoptotic cells (ACs) are swiftly removed by specialized phagocytes, such as macrophages, or nonprofessional phagocytes, such as epidermal cells. Genetic studies of model organisms such as Caenorhabditis elegans have helped to elucidate the mechanisms of AC clearance and the underlying causes of disorders related to the dysregulation of these pathways. C. elegans possesses six class B scavenger receptor homologs, but whether they affect apoptosis is unknown. Here, we show that only the loss of function of scav‐3, the C. elegans homolog of human lysosomal integral membrane protein‐2, resulted in a considerable accumulation of cell corpses, which was caused by a failure in degradation rather than engulfment. SCAV‐3 was found to be widely distributed and localized in lysosomes to maintain the integrity of the lysosomal membrane. Further study revealed that loss of scav‐3 had no effect on phagosome maturation or the recruitment of lysosomes to phagosomes carrying cell corpses. Moreover, we discovered that the hydrolytic enzymes contained in the lysosomes were reduced in phagosomes in scav‐3 mutants. Thus, hydrolases may leak from the damaged lysosome during phagolysosome formation due to the loss of scav‐3 function, which reduces lysosome digestion activity and thus directly contributes to the elimination of ACs. [ABSTRACT FROM AUTHOR]

Copyright of Guangdong Agricultural Sciences is the property of South China Agricultural University, Guangdong Academy of Agricultural Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Non-traumatic intraparenchymal brain hemorrhage is referred to as intracerebral hemorrhage (ICH). Although ICH is associated with a high rate of disability and case fatality, active intervention can significantly lower the rate of severe disability. Studies have shown that the speed of hematoma clearance after ICH determines the patient's prognosis. Following ICH, depending on the hematoma volume and mass effect, either surgical-ormedication-only conservative treatment is chosen. The goal of promoting endogenous hematoma absorption is more relevant because surgery is only appropriate for a small percentage of patients, and open surgery can cause additional trauma to patients. The primary method of removing hematoma after ICH in the future will involve understanding how to produce and manage macrophage/microglial endogenous phagocytic hematomas. Therefore, it is necessary to elucidate the regulatory mechanisms and key targets for clinical purposes. [ABSTRACT FROM AUTHOR]

The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α+ dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α+ DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens. The absence of CD8α+ DCs or CD36 altered thymic T cell selection, as evidenced by TCR repertoire analysis and the loss of allo-tolerance in murine allogeneic BM transplantation (allo-BMT) studies. Decreases in these DCs and CD36 expression in peripheral blood of human allo-BMT patients correlated with graft-versus-host disease. Our findings suggest that CD36 facilitates transfer of mTEC-derived cell-surface antigen on CD8α+ DCs to promote tolerance to host antigens during homeostasis and allo-BMT.

Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitute up to 50% of the cell mass of human tumors. TAMs interact with the components of the tumor microenvironment (TME) by using scavenger receptors (SRs), a large superfamily of multifunctional receptors that recognize, internalize and transport to the endosomal/lysosomal pathway apoptotic cells, cytokines, matrix molecules, lipid modified lipoproteins and other unwanted-self ligands. In our review, we summarized state-of-the art for the role of macrophage scavenger receptors in tumor development and their significance as cancer biomarkers. In this review we focused on functional activity of TAM-expressing SRs in animal models and in patients, and summarized the data for different human cancer types about the prognostic significance of TAM-expressed SRs. We discussed the role of SRs in the regulation of cancer cell biology, cell-cell and cell-matrix interaction in TME, immune status in TME, angiogenesis, and intratumoral metabolism. Targeting of tumor-promoting SRs can be a promising therapeutic approach in anticancer therapy. In our review we provide evidence for both tumor supporting and tumor inhibiting functions of scavenger receptors expressed on TAMs. We focused on the key differences in the prognostic and functional roles of SRs that are specific for cancer types. We highlighted perspectives for inhibition of tumor-promoting SRs in anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection. Methods: We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM–NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM–NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. Results: AM–NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM–NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ. Conclusions: The AM–NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitute up to 50% of the cell mass of human tumors. TAMs interact with the components of the tumor microenvironment (TME) by using scavenger receptors (SRs), a large superfamily of multifunctional receptors that recognize, internalize and transport to the endosomal/lysosomal pathway apoptotic cells, cytokines, matrix molecules, lipid modified lipoproteins and other unwanted-self ligands. In our review, we summarized state-of-the art for the role of macrophage scavenger receptors in tumor development and their significance as cancer biomarkers. In this review we focused on functional activity of TAM-expressing SRs in animal models and in patients, and summarized the data for different human cancer types about the prognostic significance of TAM-expressed SRs. We discussed the role of SRs in the regulation of cancer cell biology, cell-cell and cell-matrix interaction in TME, immune status in TME, angiogenesis, and intratumoral metabolism. Targeting of tumor-promoting SRs can be a promising therapeutic approach in anti-cancer therapy. In our review we provide evidence for both tumor supporting and tumor inhibiting functions of scavenger receptors expressed on TAMs. We focused on the key differences in the prognostic and functional roles of SRs that are specific for cancer types. We highlighted perspectives for inhibition of tumor-promoting SRs in anti-cancer therapy.

Scavenger receptors (SRs) are a structurally heterogeneous superfamily of evolutionarily conserved receptors that are divided into classes A to J. SRs can recognize multiple ligands, such as modified lipoproteins, damage‐associated molecular patterns, and pathogen‐associated molecular patterns, and regulate lipid metabolism, immunity, and homeostasis. According to the literature, SRs may play a critical role in myocardial infarction and ischemia/reperfusion injury, and the soluble types of SRs may be a series of promising biomarkers for the diagnosis and prognosis of patients with acute coronary syndrome or acute myocardial infarction. In this review, we briefly summarize the structure and function of SRs and discuss the association between each SR and ischemic cardiac injury in patients and animal models in detail. A better understanding of the effect of SRs on ischemic cardiac injury will inspire novel ideas for therapeutic drug discovery and disease evaluation in patients with myocardial infarction.

Identifying the genetic bases for colour patterns has provided important insights into the control and expression of pigmentation and how these characteristics influence fitness. However, much more is known about the genetic bases for traits based on melanin pigments than for traits based on another major class of pigments, carotenoids. Here, we use natural admixture in a hybrid zone between Audubon's and myrtle warblers (Setophaga coronata auduboni/S. c. coronata) to identify genomic regions associated with both types of pigmentation. Warblers are known for rapid speciation and dramatic differences in plumage. For each of five plumage coloration traits, we found highly significant associations with multiple single-nucleotide polymorphisms (SNPs) across the genome and these were clustered in discrete regions. Regions near significantly associated SNPs were enriched for genes associated with keratin filaments, fibrils that make up feathers. A carotenoid-based trait that differs between the taxa-throat colour-had more than a dozen genomic regions of association. One cluster of SNPs for this trait overlaps the Scavenger Receptor Class F Member 2 (SCARF2) gene. Other scavenger receptors are presumed to be expressed at target tissues and involved in the selective movement of carotenoids into the target cells, making SCARF2 a plausible new candidate for carotenoid processing. In addition, two melanin-based plumage traits-colours of the eye line and eye spot-show very strong associations with a single genomic region mapping to chromosome 20 in the zebra finch. These findings indicate that only a subset of the genomic regions differentiated between these two warblers are associated with the plumage differences between them and demonstrate the utility of reduced-representation genomic scans in hybrid zones.

Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers. Next, we designed a nanotechnology approach to regulate SR-mediated intracellular ASYN trafficking within microglia. We synthesized mucic acid-derivatized sugar-based amphiphilic molecules (AM) with optimal stereochemistry, rigidity, and charge for enhanced dual binding affinity to SRs and fabricated serum-stable nanoparticles via flash nanoprecipitation comprising hydrophobe cores and amphiphile shells. Treatment of microglia with AM nanoparticles decreased monomeric ASYN internalization and intracellular ASYN oligomer formation. We then engineered composite deactivating NPs with dual character, namely shell-based SR-binding amphiphiles, and core-based antioxidant poly (ferrulic acid), to investigate concerted inhibition of oxidative activation. In ASYN-challenged microglia treated with NPs, we observed decreased ASYN-mediated acute microglial activation and diminished microglial neurotoxicity caused by exposure to aggregated ASYN. When the composite NPs were administered in vivo within the substantia nigra of fibrillar ASYN-challenged wild type mice, there was marked attenuation of activated microglia. Overall, SR-targeting AM nanotechnology represents a novel paradigm in alleviating microglial activation in the context of synucleinopathies like PD and other neurodegenerative diseases.

Lipid accumulation and inflammation act together to induce, sustain, and further development of chronic liver disease. Hepatitis C virus (HCV) infection induces metabolic and immune changes in liver macrophages, promoting lipid accumulation and inflammation that synergize and culminate in the development of steatohepatitis and fibrogenesis. Chronic HCV patients have increased liver macrophages with disruptions in cholesterol metabolism and alterations in inflammatory mediators. While HCV-induced changes in inflammatory mediators are well documented, how HCV triggers metabolic change in macrophages is unknown. In this report, we examined the mechanism of macrophage sensing of HCV to cause metabolic impairment and subsequent immune dysfunction. We demonstrate that HCV protein and RNA kinetics in macrophages are distinct from hepatocytes. In macrophages, HCV RNAs and protein accumulate rapidly after exposure but internalized RNAs quickly decline to a low-level set point. Notably, exposure of macrophages to HCV resulted in increased lipids and cholesterol and activation of cholesterol-sensing, immunomodulatory liver X receptors (LXRs). Furthermore, we provide evidence that HCV RNA accumulation in macrophages occurs through scavenging receptors. These results suggest that HCV released from infected hepatocytes stimulates accumulation of lipids and activation of LXR in macrophages contributing to metabolic changes involved in HCV-induced chronic liver disease. Our results provide novel insight into mechanisms through which impaired lipid metabolism in macrophages associated with HCV infection promotes development of liver steatohepatitis and fibrosis. [ABSTRACT FROM AUTHOR]

Severe equine asthma (SEA) is a common, debilitating lower airway inflammatory disorder of older horses. Alveolar macrophages (AMs) survey inhaled particulates from barn sources causing them to switch from an anti-inflammatory to a proinflammatory phenotype, resulting in neutrophil recruitment to the lung. This proinflammatory switch may contribute to the development and prolongation of SEA. Validated antibodies to identify the cells involved in the pathogenesis of SEA are lacking. In this study, monoclonal antibodies against CD90, CD163, and CD206 were tested for reactivity with equine leukocytes by immunocytochemistry and flow cytometry. A multi-color flow cytometric assay was developed to identify leukocytes in equine bronchoalveolar lavage fluid (BALF). Four control and 4 SEA-susceptible horses had BALF collected before and after a 48-hour moldy hay challenge. Antibodies against CD90 uniquely labeled equine neutrophils, and antibodies against CD163 and CD206 identified equine macrophages. Postchallenge AM surface expression of CD163 increased in both groups of horses, but the increase was statistically significant in only the SEA-susceptible group (P =.02). The surface expression of CD206 on AMs increased significantly in the SEA-susceptible group (P =.03) but was unchanged in the control group (P =.5). Increased expression of CD163 and CD206 during exacerbation of SEA suggested an association between AM phenotype and lung inflammation. However, functions of AMs in the pathogenesis of SEA remain to be elucidated. [ABSTRACT FROM AUTHOR]

Although class B scavenger receptors (SR-Bs) in mammals are multifunctional molecules, the functions of SR-Bs in invertebrates remain largely unknown. In this study, we characterized an SR-B homolog, namely Sp SR-B2, from Scylla paramamosain. Sp SR-B2 shared high similarity with mammalian SR-Bs, and exhibited specific binding activity to ac-LDL, indicating that it may be a new member of SR-B class in invertebrates. SpSR-B2 was upregulated after challenge with white spot syndrome virus (WSSV) or bacteria. Binding assays showed that Sp SR-B2 specifically interacted with WSSV envelope protein VP24. Besides, Sp SR-B2 could bind to all tested bacterial cells and agglutinate these bacteria. Sp SR-B2 also exhibited a strong binding activity to LPS but weak binding activities to other tested polysaccharides. These findings indicated that Sp SR-B2 was a potential recognition molecule for viral protein VP24 and bacterial LPS. Knockdown of SpSR-B2 resulted in dramatically decreased expressions of certain antimicrobial peptides (AMPs), and overexpression of Sp SR-B2 led to the increased expression of the AMP of Sp ALF2, suggesting that Sp SR-B2 could regulate the expression of AMPs. Taken together, this study revealed that Sp SR-B2 functioned as a potential pattern recognition receptor participating in antiviral and antibacterial immunity, and provided new insights into the immune functions of invertebrate SR-Bs. • Sp SR-B2 specifically interacted with WSSV envelope protein VP24. • Sp SR-B2 displayed strong binding activity to LPS. • Sp SR-B2 regulated the expressions of certain AMPs. • Sp SR-B2 functioned as a potential PRR participating in antiviral and antibacterial immunity. [ABSTRACT FROM AUTHOR]

Macrophages are key innate immune cells that mediate implant acceptance or rejection. Titanium implants degrade over time inside the body, which results in the release of implant wear-off particles. Titanium nanoparticles (TiNPs) favor pro-inflammatory macrophage polarization (M1) and lower tolerogenic activation (M2). GDF-15 regulates immune tolerance and fibrosis and is endocytosed by stabilin-1. How TiNPs affect the healing activities of macrophages and their release of circulating cytokines is an open question in regenerative medicine. In this study for the first time, we identified the transcriptional program induced and suppressed by TiNPs in human pro-inflammatory and healing macrophages. Microarray analysis revealed that TiNPs altered the expression of 5098 genes in M1 (IFN-γ-stimulated) and 4380 genes in M2 (IL-4–stimulated) macrophages. 1980 genes were differentially regulated in both M1 and M2. Affymetrix analysis, confirmed by RT-PCR, demonstrated that TiNPs upregulate expression of GDF-15 and suppress stabilin-1, scavenger receptor of GDF-15. TiNPs also significantly stimulated GDF-15 protein secretion in inflammatory and healing macrophages. Flow cytometry demonstrated, that scavenging activity of stabilin-1 was significantly suppressed by TiNPs. Confocal microscopy analysis showed that TiNPs impair internalization of stabilin-1 ligand acLDL and its transport to the endocytic pathway. Our data demonstrate that TiNPs have a dual effect on the GDF-15/stabilin-1 interaction in macrophage system, by increasing the production of GDF-15 and suppressing stabilin-1-mediated clearance function. In summary, this process can result in a significant increase of GDF-15 in the extracellular space and in circulation leading to unbalanced pro-fibrotic reactions and implant complications. [ABSTRACT FROM AUTHOR]

Macrophages are key innate immune cells that mediate implant acceptance or rejection. Titanium implants degrade over time inside the body, which results in the release of implant wear-off particles. Titanium nanoparticles (TiNPs) favor pro-inflammatory macrophage polarization (M1) and lower tolerogenic activation (M2). GDF-15 regulates immune tolerance and fibrosis and is endocytosed by stabilin-1. How TiNPs affect the healing activities of macrophages and their release of circulating cytokines is an open question in regenerative medicine. In this study for the first time, we identified the transcriptional program induced and suppressed by TiNPs in human pro-inflammatory and healing macrophages. Microarray analysis revealed that TiNPs altered the expression of 5098 genes in M1 (IFN-γ-stimulated) and 4380 genes in M2 (IL-4–stimulated) macrophages. 1980 genes were differentially regulated in both M1 and M2. Affymetrix analysis, confirmed by RT-PCR, demonstrated that TiNPs upregulate expression of GDF-15 and suppress stabilin-1, scavenger receptor of GDF-15. TiNPs also significantly stimulated GDF-15 protein secretion in inflammatory and healing macrophages. Flow cytometry demonstrated, that scavenging activity of stabilin-1 was significantly suppressed by TiNPs. Confocal microscopy analysis showed that TiNPs impair internalization of stabilin-1 ligand acLDL and its transport to the endocytic pathway. Our data demonstrate that TiNPs have a dual effect on the GDF-15/stabilin-1 interaction in macrophage system, by increasing the production of GDF-15 and suppressing stabilin-1-mediated clearance function. In summary, this process can result in a significant increase of GDF-15 in the extracellular space and in circulation leading to unbalanced pro-fibrotic reactions and implant complications.

The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively “silenced” by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease.

The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively "silenced" by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease. [ABSTRACT FROM AUTHOR]

The definition of scavenger endothelial cells (SEC) is exclusively based on functional and structural characteristics. The following characteristics are common hallmarks for the vertebrate SEC: (a) All vertebrates examined are furnished with a population of special SEC that plays a role in the catabolism of physiologic and non‐physiologic soluble waste macromolecules. (b) From the ligands that are endocytosed, SEC in all seven vertebrate classes appear to express the collagen α‐chain receptor and the scavenger receptors. In addition, the hyaluronan and the mannose receptors are present on SEC of mammalia (several species) and osteichthyes (e.g., salmon and cod). It is likely that all four receptor types are present in all vertebrate classes. (c) Like liver endothelial cells (LEC) in mammals, SEC in all vertebrate classes are geared to endocytosis of soluble macromolecules, but phagocytic uptake of particles is taken care of mainly by macrophages. (d) The most primitive vertebrates (hagfish, lamprey and ray) carry their SEC in gill vessels, whereas phylogenetically younger fishes (salmon, carp, cod and plaice) carry their SEC in either kidney or heart and in all terrestrial vertebrates—SEC are found exclusively in the liver. (e) SEC of all vertebrates are localized in blood sinusoids or trabeculae that carry large amounts of slowly flowing and O2 poor blood. (f) SEC differs functionally and structurally from what is normally associated with "conventional vascular endothelium." [ABSTRACT FROM AUTHOR]

Atherosclerosis, an inflammatory lipid-rich plaque disease is perpetuated by the unregulated scavenger-receptor-mediated uptake of oxidized lipoproteins (oxLDL) in macrophages. Current treatments lack the ability to directly inhibit oxLDL accumulation and foam cell conversion within diseased arteries. In this work, we harness nanotechnology to design and fabricate a new class of nanoparticles (NPs) based on hydrophobic mucic acid cores and amphiphilic shells with the ability to inhibit the uncontrolled uptake of modified lipids in human macrophages. Our results indicate that tailored NP core and shell formulations repress oxLDL internalization via dual complementary mechanisms. Specifically, the most atheroprotective molecules in the NP cores competitively reduced NP-mediated uptake to scavenger receptor A (SRA) and also down-regulated the surface expression of SRA and CD36. Thus, nanoparticles can be designed to switch activated, lipid-scavenging macrophages to antiatherogenic phenotypes, which could be the basis for future antiatherosclerotic therapeutics.

Mona Ahmed,1 Roland Baumgartner,2 Silvia Aldi,3 Philip Dusart,4 Ulf Hedin,1 Björn Gustafsson,1 Kenneth Caidahl1,51Department of Molecular Medicine and Surgery, Karolinska Institutet, SE 17176, Stockholm, Sweden; 2Department of Medicine Solna, Karolinska Institutet, SE 17176, Stockholm, Sweden; 3Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 17177, Stockholm, Sweden; 4Department of Cellular and Clinical Proteomics, Science for Life Laboratory, Kungliga Tekniska Högskolan (KTH), SE 17165, Stockholm, Sweden; 5Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE 41345, Gothenburg, SwedenBackground: Inflammation and accumulation of macrophages are key features of unstable atherosclerotic plaques. The ability of macrophages to take up molecular probes can be exploited in new clinical imaging methods for the detection of unstable atherosclerotic lesions. We investigated whether modifications of human serum albumin (HSA) could be used to target macrophages efficiently in vitro.Materials and methods: Maleylated and aconitylated HSA were compared with unmodified HSA. Fluorescent or radiolabeled (89Zr) modified HSA was used in in vitro experiments to study cellular uptake by differentiated THP-1 cells and primary human macrophages. The time course of uptake was evaluated by flow cytometry, confocal microscopy, real-time microscopy and radioactivity measurements. The involvement of scavenger receptors (SR-A1, SR-B2, LOX-1) was assessed by knockdown experiments using RNA interference, by blocking experiments and by assays of competition by modified low-density lipoprotein.Results: Modified HSA was readily taken up by different macrophages. Uptake was mediated nonexclusively via the scavenger receptor SR-A1 (encoded by the MSR1 gene). Knockdown of CD36 and ORL1 had no influence on the uptake. Modified HSA was preferentially taken up by human macrophages compared with other vascular cell types such as endothelial cells and smooth muscle cells.Conclusions: Modified 89Zr-labeled HSA probes were recognized by different subsets of polarized macrophages, and maleylated HSA may be a promising radiotracer for radionuclide imaging of macrophage-rich inflammatory vascular diseases.Keywords: atherosclerosis, inflammation, macrophage, molecular imaging, scavenger receptor, zirconium

Accumulation of cholesterol‐laden macrophage foam cells characteristic of early stage atherosclerotic lesions. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate found in cruciferous vegetables that has reported a variety of activities including antioxidant and anti‐inflammatory properties. However, the protective effect of PEITC on foam cell formation and its precise mechanism is not yet clear. Therefore, we investigated whether PEITC suppresses foam cell formation and regulates the expression of genes related to lipid accumulation, cholesterol efflux, and inflammation in THP‐1 derived‐macrophages. We exposed THP‐1 derived‐macrophages to oxidized low‐density lipoprotein (ox‐LDL) (20 μg/mL) and lipopolysaccharide (LPS) (500 ng/ml) to mimic foam cell formation. Here, PEITC downregulated the expression of lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), cluster of differentiation 36 (CD36), scavenger receptor A1 (SR‐A1), and nuclear factor‐κB (NF‐κB), while upregulated ATP binding cassette subfamily A member 1 (ABCA1)/liver‐X‐receptor α (LXR‐α)/peroxisome proliferator‐activated receptor gamma (PPARγ) and sirtuin 1 (SIRT1) expression compared to co‐treated with ox‐LDL and LPS. Taken together, PEITC, at least in part, inhibits foam cell formation and reduces lipid accumulation in foam cells. Therefore, we suggest that PEITC may be a potential candidate for the treatment and prevention of vascular inflammation and atherosclerosis. [ABSTRACT FROM AUTHOR]