Role Of Macrophage Scavenger Receptor Research Articles

Role of macrophage scavenger receptor 1 in the progression of dyslipidemia in acne vulgaris patients.

Macrophage scavenger receptor 1 gene (MSR1), is responsible for producing macrophage scavenger receptors. MSR1 is primarily located on the surfaces of various macrophage types and is known to exert a range of effects on the human body. These effects include influencing innate and adaptive immunological reactions, as well as contributing to the development of conditions such as atherosclerosis, dyslipidemia, liver and lung disease, and cancer. The unregulated assimilation of lipoproteins by MSR1 leads to the creation of macrophages rich in cholesterol that manifest as foam-like cells, ultimately contributing to dyslipidemia. This occurrence highlights the significance of MSR1 as a key player in the pathophysiology of dyslipidemia. In this study, we aimed to estimate variation in lipid profile in acne vulgaris (AV) patients. Also, we aimed to investigate the role of MSR1 in lipid profile variation. A case-control study consisting of 100 patients with AV and 104 healthy controls. Lipid profiles were assessed using normalized enzymatic processes and genotype analyses were performed by a polymerase chain reaction and standard Sanger sequencing. Predictions of variant effects were performed using in silico tools. Our results indicated that the levels of lipid profile were higher in patients with AV than in healthy patients. The two haplotypes that were most prevalent in the patients were TCAC (16.5%) and CAGG (15.47%), whereas the two haplotypes that were more prevalent in the controls were TAAC (16.43%) and CCAC (15.62%). IVS5.59 C>A and rs433235 A>G are in linkage disequilibrium. Additionally, rs433235 A>G has a significant linkage disequilibrium with rs3747531 C>G. In silico analysis, tools indicated that the rs433235 A>G variant was disease-causing. Patients diagnosed with TCAC and CAGG exhibited a higher prevalence compared to healthy patients with TAAC and CCAC. The linkage disequilibrium between rs433235 A>G and IVS5.59 C>A has been established. Furthermore, there appears to be significant linkage disequilibrium between rs3747531 C>G and rs433235 A>G. These findings support the notion that genetic variations may play a critical role in the pathogenesis of these conditions.

“The role of macrophage scavenger receptors in engineered biomaterial scaffold remodeling”

Abstract CD206, also known as mannose receptor C type 1, is used frequently as a marker to identify the M2 polarized macrophages in the investigation of immune responses to biomaterials. M2 macrophages help with tissue repair, inflammation reduction, building immune tolerance, and defense against excessive inflammation. CD206 is found on the surface of M2 macrophages and dendritic cells, and functions as a pattern recognition receptor for a variety of connective tissues in health, including pulmonary tuberculosis, liver fibrosis, and others. Previous research has shown a role of CD206 in internalization of collagen fragments in tumors. In this study, we aim to determine whether CD206 is more than just an M2 marker in response to biomaterials. We have found that adaptive immune cells as well as cross-presenting dendritic cells are critical for CD206 induction in biomaterial-treated muscle injury. In Batf3−/− mice, where CD206 expression is lost, we find hemosiderin deposition suggesting defects in phagocytosis. In future studies, we will use CD206-deficient to directly evaluate its role in scaffold remodeling at the site of injury.

Macrophage scavenger receptors: Tumor support and tumor inhibition.

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.

The role of macrophage scavenger receptor 1 (MSR1) in inflammatory disorders and cancer

Macrophage scavenger receptor 1 (MSR1), also named CD204, holds key inflammatory roles in multiple pathophysiologic processes. Present primarily on the surface of various types of macrophage, this receptor variably affects processes such as atherosclerosis, innate and adaptive immunity, lung and liver disease, and more recently, cancer. As highlighted throughout this review, the role of MSR1 is often dichotomous, being either host protective or detrimental to the pathogenesis of disease. We will discuss the role of MSR1 in health and disease with a focus on the molecular mechanisms influencing MSR1 expression, how altered expression affects disease process and macrophage function, the limited cell signalling pathways discovered thus far, the emerging role of MSR1 in tumour associated macrophages as well as the therapeutic potential of targeting MSR1.

Comprehensive analysis of the prognostic and role in immune cell infiltration of MSR1 expression in lower-grade gliomas.

BackgroundThe therapeutic effects of conventional treatment on gliomas are not promising. The tumor microenvironment (TME) has a close association with the invasiveness of multiple types of tumors, including low‐grade gliomas (LGG). This study aims to validate the prognostic and immune‐related role of macrophage scavenger receptor 1 (MSR1) in LGG patients.MethodsData in this study were obtained from public databases. The differential expression of MSR1 was analyzed in LGG patients with different clinicopathological characteristics. Kaplan–Meier survival analysis, a time‐dependent receiver operating characteristic (ROC) curve, and Cox regression analysis were used to assess the prognostic value of MSR1. Differentially expressed genes (DEGs) were screened between the high and low expression groups of MSR1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to annotate the function of these DEGs. Hallmark gene sets were identified based on MSR1 by Gene Set Enrichment Analysis (GSEA). Difference analysis and correlation analysis were used to study the relationship between MSR1 and TME‐related scores, tumor‐infiltrating immune cells (TIICs), immune‐related gene sets, and immune checkpoints (ICPs). The single‐cell sequencing data were processed to identify the cell types expressing MSR1. The quantification of TIICs in TME was calculated by single‐sample gene set enrichment analysis (ssGSEA). The differential expression of MSR1 in LGG and control brain tissues was verified by experiments.ResultsThere were significant differences in the expression level of MSR1 in different types of tissues and cells. MSR1 has a high prognostic value in LGG patients and can be used as an independent prognostic factor. MSR1 is closely related to TME and may play an important role in the immunotherapy of LGG patients.ConclusionsThe result of our study demonstrated that MSR1 is an independent prognostic biomarker in LGG patients and may play an important role in the TME of LGGs.

Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and exvivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. Invitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice.

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

The progression of prion diseases is accompanied by the accumulation of prions in the brain. Ablation of microglia enhances prion accumulation and accelerates disease progression, suggesting that microglia play a neuroprotective role by clearing prions. However, the mechanisms underlying the phagocytosis and clearance of prion are largely unknown. The macrophage scavenger receptor 1 (Msr1) is an important phagocytic receptor expressed by microglia in the brain and is involved in the uptake and clearance of soluble amyloid-β. We therefore asked whether Msr1 might play a role in prion clearance and assessed the scavenger function of Msr1 in prion pathogenesis. We found that Msr1 expression was upregulated in prion-infected mouse brains. However, Msr1 deficiency did not change prion disease progression or lesion patterns. Prion deposition in Msr1 deficient mice was similar to their wild-type littermates. In addition, prion-induced neuroinflammation was not affected by Msr1 ablation. We conclude that Msr1 does not play a major role in prion pathogenesis.Key messagesMsr1 expression is upregulated in prion-infected mouse brains at the terminal stageMsr1 deficiency does not affect prion disease progressionMsr1 does not play a major role in prion clearance or prion pathogenesisMicroglia-mediated phagocytosis and clearance of Aβ and prion may adopt distinct molecular pathways

Sirt6 deletion in bone marrow-derived cells increases atherosclerosis – Central role of macrophage scavenger receptor 1

AimsSirtuin 6 (Sirt6) is a NAD+-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model. Methods and resultsSirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe−/− mice fed a high-cholesterol diet for 12 weeks (n = 12–14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels. ConclusionsLoss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.

Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3β/β-catenin pathway.

Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention.Methods: The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) in vivo. The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing.Results: In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3β/β-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation.Conclusion: Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.

The Role of Macrophage Class A Scavenger Receptors in a Laser-Induced Murine Choroidal Neovascularization Model

Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A(-/-)), MARCO (MARCO(-/-)), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. Wild-type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1- and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice. The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD.

Major Vault Protein Regulates Class A Scavenger Receptor-mediated Tumor Necrosis Factor-α Synthesis and Apoptosis in Macrophages

Atherosclerosis is considered a disease of chronic inflammation largely initiated and perpetuated by macrophage-dependent synthesis and release of pro-inflammatory mediators. Class A scavenger receptor (SR-A) expressed on macrophages plays a key role in this process. However, how SR-A-mediated pro-inflammatory response is modulated in macrophages remains ill defined. Here through immunoprecipitation coupled with mass spectrometry, we reported major vault protein (MVP) as a novel binding partner for SR-A. The interaction between SR-A and MVP was confirmed by immunofluorescence staining and chemical cross-linking assay. Treatment of macrophages with fucoidan, a SR-A ligand, led to a marked increase in TNF-α production, which was attenuated by MVP depletion. Further analysis revealed that SR-A stimulated TNF-α synthesis in macrophages via the caveolin- instead of clathrin-mediated endocytic pathway linked to p38 and JNK, but not ERK, signaling pathways. Importantly, fucoidan invoked an enrichment of MVP in lipid raft, a caveolin-reliant membrane structure, and enhanced the interaction among SR-A, caveolin, and MVP. Finally, we demonstrated that MVP elimination ameliorated SR-A-mediated apoptosis in macrophages. As such, MVP may fine-tune SR-A activity in macrophages which contributes to the development of atherosclerosis.

Role of macrophage scavenger receptors in atherosclerosis

Accumulating evidence indicates that atherosclerosis is a chronic inflammatory disease. The key innate immune cells that are involved in the pathogenesis of atherosclerosis are circulating monocytes and plaque macrophages. Complex interplay between immune and metabolic processes results in pathological activity of these cells. The best understood pathological process mediated by macrophages is their inability to process modified lipoproteins properly resulting in the formation of foamy cells, which are a dangerous component of atherosclerotic plaques. Key molecules involved in the recognition and processing of modified lipoproteins are scavenger receptors (SR). This is a large family of surface expressed structurally heterogeneous receptors with a broad spectrum of endogenous and exogenous ligands. The common functional feature of SR is internalisation of extracellular components and targeting them for lysosomal degradation. However, these relatively simple functions can have complex consequences, since they are linked to diverse specific signalling pathways and to other membrane transport pathways. Moreover, scavenger receptors can co-operate with other types of receptors increasing the variability of the macrophage response to multiple extracellular ligands. At least some SRs respond to modified lipoproteins by amplification of inflammation and accumulation of macrophages in the plaque, while some SRs may support tolerogenic reactions. Outcome of different SR activities will be the decision of monocytes and macrophage to guard homeostatic balance, support atherosclerosis progression and plaque instability by inflammatory reactions, or support rapid fibrotic processes in the plaque that stabilise it. Despite the accumulating knowledge about the molecular mechanisms of scavenger receptor action, their role in the progression of atherosclerosis remains controversial. The activities of scavenger receptors that can contribute to each of these processes are a subject of current review.

Abstract 4634: Decreased infiltration of macrophage scavenger receptor in non-malignant biopsy specimens is associated with detection of prostate cancer

Abstract INTRODUCTION AND OBJECTIVE: Screening for prostate cancer (PCA) has become widespread practice. Many men with negative biopsy findings undergo repeat biopsies to rule out PCA. It should be long enough to avoid unnecessary biopsies and costs. The discovery of new predictors is essential to establish appropriate repeat biopsies. Several predictors of subsequent PCA detection have been described. Especially, chronic inflammation is considered to be a risk factor for PCA. The macrophage scavenger receptor (MSR) has been reported to play a role in recognizing foreign pathogenic substances. MSR-positive inflammatory cells are often seen in solid tumors. Tumor-associated macrophages (TAM) have been shown to positively or negatively regulate the growth of various malignant cells. However, the role of MSR and TAM in PCA carcinogenesis is unclear. In the present study, infiltration of MSR and TAM in non-malignant biopsy specimens was evaluated as a possible predictive value for PCA. METHODS: These reviews were evaluated for 92 patients ranging from 51 to 82 years (median, 69 years), who received repeat needle biopsies of the prostate and were diagnosed as non-malignant during first biopsy. Of these, 30 (32.6%) were positive for cancer during second or third biopsy. TAM and MSR were immunohistochemically labeled using a monoclonal (CD68 and CD204) antibody. For systematic counting, 6 ocular measuring fields were randomly chosen under a microscope at a power of × 400 within first negative biopsy specimens. RESULTS: There were no significant differences in PSA, Age and Interval of previous and subsequent biopsies, between negative and positive cases for cancer. Median count of MSR and TAM in each case was 32 and 16. MSR count in patients with cancer was lower than in patients without cancer (P &amp;lt; 0.001). However, in TAM count there were no significant differences between patients with or without cancer. CONCLUSION: Decreased infiltration of MSR in non-malignant biopsy is associated with detection of PCA. MSR is predictor for appropriate repeat biopsies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4634.

Role of Macrophage Scavenger Receptors in Response to Listeria monocytogenes Infection in Mice

Type I and type II macrophage scavenger receptors (SR-A I/II) recognize a variety of polyanions including bacterial cell-wall products such as lipopolysaccharide, suggesting a role for SR-A I/II in immunity against bacterial infection. SR-A I/II-deficient (MSR-A-/-) mice were more susceptible to infection with listeriolysin-O (LLO)-producing Listeria monocytogenes. After infection, Kupffer cells in wild-type (MSR-A+/+) mice phagocytized larger numbers of Listeria than those in MSR-A-/- mice. The number and the diameter of hepatic granulomas were larger in MSR-A-/- mice than MSR-A+/+ mice. L. monocytogenes replicated at higher levels in the liver of MSR-A-/- mice compared with MSR-A+/+ mice, and macrophages from MSR-A-/- mice showed impaired ability to kill Listeria in vitro. However, macrophages from MSR-A+/+ and MSR-A-/- mice showed similar levels of listericidal activity against isogenic mutant L. monocytogenes with an inactivated LLO gene. The listerial phagocytic activities of MSR-A+/+ macrophages treated with an anti-SR-A I/II antibody (2F8) and MSR-A-/- macrophages were significantly impaired compared with untreated MSR-A+/+ macrophages, indicating that SR-A I/II function as a receptor for L. monocytogenes. Electron microscopy revealed that most L. monocytogenes had been eliminated from the lysosomes of MSR-A+/+ macrophages in vivo and in vitro. In contrast, L. monocytogenes rapidly lysed the phagosomal membrane and escaped to the cytosol in MSR-A-/- macrophages and in MSR-A+/+ macrophages treated with 2F8 before phagosome-lysosome fusion. These findings imply that SR-A I/II plays a crucial role in host defense against listerial infection not only by functioning as a receptor but also by mediating listericidal mechanisms through the regulation of LLO-dependent listerial escape from the macrophages.

Role of macrophage scavenger receptor in endotoxin shock

Lipopolysaccharide (LPS) is known to bind to several receptors on macrophages, including CD14 and macrophage scavenger receptor class A types I and II (MSR-A), and stimulates macrophages to release various inflammatory mediators. MSR-A recognizes a broad range of polyanionic ligands such as chemically modified lipoproteins, LPS of Gram-negative bacteria, and lipoteichoic acid of Gram-positive bacteria, suggesting a role in host defence. In this study, mice lacking MSR-A were used to elucidate the role of MSR-A in endotoxin shock. Peritoneal macrophages from MSR-A-deficient (MSR-A−/−) mice bound less remarkably to LPS than those from wild-type (MSR-A+/+) mice and the binding activity of MSR-A+/+ macrophages to LPS was reduced by the addition of an anti-MSR-A antibody. Clearance of LPS in serum was retarded in MSR-A−/− mice after intraperitoneal administration of LPS. LPS-induced expression of cytokines in the liver was similar in MSR-A+/+ and MSR-A−/− mice, but levels of interleukin (IL)-1β expression and serum IL-1β were lower in MSR-A−/− mice. Administration of large doses of LPS resulted in a higher mortality of MSR-A+/+ mice and pretreatment with an IL-1 receptor antagonist reduced the mortality. Thus, MSR-A-mediated macrophage activation plays a negative role in protecting mice from endotoxin shock by enhancing IL-1β production by macrophages. Copyright © 2000 John Wiley & Sons, Ltd.

Role of macrophage scavenger receptor in endotoxin shock

Lipopolysaccharide (LPS) is known to bind to several receptors on macrophages, including CD14 and macrophage scavenger receptor class A types I and II (MSR-A), and stimulates macrophages to release various inflammatory mediators. MSR-A recognizes a broad range of polyanionic ligands such as chemically modified lipoproteins, LPS of Gram-negative bacteria, and lipoteichoic acid of Gram-positive bacteria, suggesting a role in host defence. In this study, mice lacking MSR-A were used to elucidate the role of MSR-A in endotoxin shock. Peritoneal macrophages from MSR-A-deficient (MSR-A(-/-)) mice bound less remarkably to LPS than those from wild-type (MSR-A(+/+)) mice and the binding activity of MSR-A(+/+) macrophages to LPS was reduced by the addition of an anti-MSR-A antibody. Clearance of LPS in serum was retarded in MSR-A(-/-) mice after intraperitoneal administration of LPS. LPS-induced expression of cytokines in the liver was similar in MSR-A(+/+) and MSR-A(-/-) mice, but levels of interleukin (IL)-1beta expression and serum IL-1beta were lower in MSR-A(-/-) mice. Administration of large doses of LPS resulted in a higher mortality of MSR-A(+/+) mice and pretreatment with an IL-1 receptor antagonist reduced the mortality. Thus, MSR-A-mediated macrophage activation plays a negative role in protecting mice from endotoxin shock by enhancing IL-1beta production by macrophages.

Role of Macrophage Scavenger Receptors in Hepatic Granuloma Formation in Mice

In mice homozygous for the gene mutation for type I and type II macrophage scavenger receptors (MSR-A), MSR-A-/-, the formation of hepatic granulomas caused by a single intravenous injection of heat-killed Corynebacterium parvum was delayed significantly for 10 days after injection, compared with granuloma formation in wild-type (MSR-A+/+) mice. In the early stage of granuloma formation, numbers of macrophages and their precursor cells were significantly reduced in MSR-A-/- mice compared with MSR-A+/+ mice. In contrast to MSR-A+/+ mice, no expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interferon-gamma mRNA was observed in MSR-A-/- mice by 3 days after injection. Also in MSR-A-/- mice, uptake of C. parvum by Kupffer cells and monocyte-derived macrophages in the early stage of granuloma formation was lower and elimination of C. parvum from the liver was slower than in MSR-A+/+ mice. In the livers of MSR-A+/+ mice, macrophages and sinusoidal endothelial cells possessed MSR-A, but this was not seen in the livers of MSR-A-/- mice. In both MSR-A-/- and MSR-A+/+ mice, expression of other scavenger receptors was demonstrated. These data suggest that MSR-A deficiency impairs the uptake and elimination of C. parvum by macrophages and delays hepatic granuloma formation, particularly in the early stage.

The role of the mouse macrophage scavenger receptor in myelin phagocytosis.

Myelin phagocytosis during Wallerian degeneration and immune-mediated demyelination depends on the action of mononuclear cells of the monocyte/macrophage system. The present study investigated the role of the macrophage scavenger receptor, a trimeric membrane glycoprotein, in myelin uptake by macrophages. Two in vitro models of myelin phagocytosis were used: an organ culture model of mouse peripheral nerves exposed to cocultured macrophages and a quantitative flow cytometric assay. Different concentrations of the monoclonal rat anti-mouse scavenger receptor antibody (2F8) were applied to these systems to selectively block the macrophage scavenger receptor. Concentration-dependent effects on macrophage migration and myelin uptake were seen when the macrophage scavenger receptor was blocked by the antibody 2F8. Low concentrations reduced myelin phagocytosis by the invading macrophages; higher concentrations completely abolished macrophage invasion of the nerves. Using a quantitative flow cytometric assay it was also shown that the 2F8 antibody inhibits phagocytosis of myelin in a dose-dependent manner. These data indicate that the macrophage scavenger receptor is involved in myelin phagocytosis by macrophages.

Advanced glycation end products and their recognition by macrophage and macrophage-derived cells.

Modification of proteins by long-term incubation with glucose leads to the formation of advanced glycation end products (AGEs). AGE proteins are taken up by macrophages via the AGE receptor, which is similar to the macrophage scavenger receptor (MSR). In the present study, we compared the ligand specificity of the AGE receptor with that of MSR by three different experiments. The endocytic uptake of 125I-acetyl-LDL by RAW cells was effectively inhibited by unlabeled AGE-bovine serum albumin (BSA), whereas the inhibitory effect of acetyl-LDL on 125I-AGE-BSA was partial. Polyanions showing an effective inhibition for endocytic uptake of AGE-BSA were not always inhibitory for endocytic degradation of acetyl-LDL. These data, together with those obtained by three-dimensional fluorescence-activated cell sorter analysis, indicate that AGE proteins are recognized by more than two receptors, of which MSR is at least one. Finally, we examined whether MSR could mediate the endocytic uptake of AGE proteins by Chinese hamster ovary cells overexpressing bovine type II MSR (CHO-SRII cells). 125I-AGE-BSA underwent endocytic degradation by CHO-SRII cells, and this was effectively inhibited by unlabeled acetyl-LDL. These results clearly show that MSR mediates the endocytic uptake of AGE proteins, suggesting a new role of MSR in biological recognition of AGE in vivo.

Colocalization of scavenger receptor in CD68 positive foam cells in verruciform xanthoma

Verruciform xanthoma is a rare variant of xanthoma that appears predominantly on oral mucosa and the anogenital area. The histologic features are characterized by marked accumulation of foam cells in the papillary dermis with verrucous epidermal acanthosis and hyperkeratosis. However, little is known of the nature or origin of foam cells. Recent studies have emphasized the crucial role of macrophage scavenger receptors in the formation of foam cells in atherogenesis. We examined the immunohistologic localization of scavenger receptors in genital verruciform xanthoma. We found that the massively infiltrated foam cells in the papillary dermis were CD68 + monocyte-macrophage lineage cells, and that the majority of CD68 + cells coexpressed scavenger receptors. The in situ staining pattern of scavenger receptor in foam cells was mainly of an intracytoplasmic vacuolar pattern similar to that of dermal resident macrophages found in normal skin. Furthermore, CDla + Langerhans cells, completely negative for scavenger receptor, were markedly decreased in number in verruciform xanthoma. These results indicate that scavenger receptor-bearing CD68 + cells are also actively involved in the development of cutaneous verruciform xanthoma, as has been shown to be the case in atherogenesis.