Disease relevance of Msr1

• These results suggest that Msr1 is involved in the regulation of the anti-inflammatory process, thus offering a new perspective on the molecular mechanisms involved in endotoxemia and sepsis [1].
• Thus, JNK2-dependent phosphorylation of SR-A promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis [2].
• In addition, MSR-A-knockout mice show an increased susceptibility to infection with Listeria monocytogenes or herpes simplex virus type-1, indicating that MSR-A may play a part in host defence against pathogens [3].
• Peritoneal macrophages from control mice phagocytose a variety of gram-positive bacteria in an SR-AI/II-dependent manner [4].
• Our findings demonstrate that SR-AI/II mediate opsonin-independent phagocytosis of gram-positive bacteria, and provide the first evidence that opsonin-independent phagocytosis plays a critical role in host defense against bacterial infections in vivo [4].

Psychiatry related information on Msr1

• In Alzheimer's disease, microglial expression of SR-A is increased [5].

High impact information on Msr1

• In wild-type macrophages, TZD treatment divergently regulated CD36 and class A macrophage-scavenger receptor expression and failed to induce significant cellular cholesterol accumulation, indicating that TZDs may not exacerbate macrophage foam-cell formation [6].
• Here we show that targeted disruption of the MSR-A gene in mice results in a reduction in the size of atherosclerotic lesions in an animal deficient in apolipoprotein E [3].
• Macrophages from MSR-A-deficient mice show a marked decrease in mLDL uptake in vitro, whereas mLDL clearance from plasma occurs at a normal rate, indicating that there may be alternative mechanisms for removing mLDL from the circulation [3].
• Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis [4].
• Type I and II class A scavenger receptors (SR-AI/II) recognize a variety of polyanions including bacterial cell wall products such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), suggesting a role for SR-AI/II in innate immunity to bacterial infections [4].

Chemical compound and disease context of Msr1

• Macrophage type-I and type-II class-A scavenger receptors (MSR-A) are implicated in the pathological deposition of cholesterol during atherogenesis as a result of receptor-mediated uptake of modified low-density lipoproteins (mLDL) [3].
• The class A scavenger receptor (SR-A) is a multifunctional trimeric membrane glycoprotein involved in atherogenesis [7].
• Deficiency of the MSR-A appears to have played an important role in generation of peripheral neuropathy with isoniazid in mice [8].

Biological context of Msr1

• Whereas MARCO was involved in opsonin-independent phagocytosis in CpG-ODN-pretreated but not in IL-4-pretreated J774 cells, anti-SR-A Abs inhibited particle uptake in untreated and IL-4-pretreated but not in CpG-ODN-pretreated cells [9].
• Our current results indicate and suggest a model for MSR ligands differentially modulating specific PK signal transduction pathways, which regulate atherogenesis-related inflammatory cytokines TNF and IL-1 [10].
• Whereas blockage of lysyl residues on apoB-100 of oxLDL by lipid peroxidation products appears to be critical for recognition by the scavenger receptor class A (SR-A), modification of the lipid moiety has been suggested to be responsible for recognition by the scavenger class B receptor, CD36 [11].
• Macrophages lacking JNK2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SR-A), whose phosphorylation was markedly decreased [2].
• As evidence, FC loading by non-SRA mechanisms activates p38 and CHOP, but not apoptosis unless the SRA is engaged [12].

Anatomical context of Msr1

• Characterization of aortic sinus lesions by electron microscopy and immunohistochemistry showed abundant macrophage foam cells, indicating that lipid uptake by intimal macrophages occurs in the absence of CD36 or SR-A [13].
• Ligation of MARCO on mouse thioglycollate-elicited peritoneal macrophages (PEMs) with immobilized mAb costimulated IL-12 production, in contrast to previously reported inhibition by SR-AI/II [9].
• Group V secretory phospholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independent process that involves cellular proteoglycans [14].
• Utilization of this permanently transfected HEK 293 cell line will allow the identification of more potent macrophage scavenger receptor antagonists, so that their utility as therapeutics for atherosclerosis can be determined [15].
• MSR-A(-/-) mice display an impaired ability to clear bacteria from the site of infection despite normal killing of S. aureus by neutrophils and die as a result of disseminated infection [4].

Associations of Msr1 with chemical compounds

• These data show that alternative lipid uptake mechanisms may contribute to macrophage cholesterol ester accumulation in vivo and suggest that the roles of SR-A and CD36 as proatherosclerotic mediators of modified LDL uptake in vivo need to be reassessed [13].
• Extensively oxidized LDL and LDL modified by exposure to fatty acid peroxidation products were efficient competitors for the uptake of labeled oxidized LDL by SR-AI/II-deficient Kupffer cells, while acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors [16].
• Following NB-DNJ treatment SR-A became Endo H-sensitive, consistent with inhibition of N-glycan processing [7].
• Glycolaldehyde, a reactive intermediate for advanced glycation end products, plays an important role in the generation of an active ligand for the macrophage scavenger receptor [17].
• When EDTA was added to chelate divalent cations, the SR-A mediated 90 and 95% of the macrophage adhesion without and with serum, respectively [18].

Physical interactions of Msr1

• The class A scavenger receptor (SR-A) binds modified lipoproteins and has been implicated in cholesterol ester deposition in macrophages [18].
• SR-A interacts with calnexin and when the association is prevented changes in the recycling kinetics and rate of turnover of the receptor result, leading to enhanced cell surface expression [7].

Regulatory relationships of Msr1

• Expression of SR-A was regulated in the opposite manner to MARCO or not affected [9].
• In conclusion, SREC-I serves as a major endocytic receptor for Ac-LDL in LPS-stimulated macrophages lacking SR-A, suggesting that it has a key role in the development of atherosclerosis in concert with SR-A [19].
• Ligation of SR-A also inhibited lipopolysaccharide plus interferon-gamma-stimulated interleukin-12 (IL-12) release, by 25% in AMs and by 68% in thioglycollate-elicited PMs, consistent with different levels of SR-A expression [20].
• Inactivation of macrophage scavenger receptor class B type I promotes atherosclerotic lesion development in apolipoprotein E-deficient mice [21].
• Phagocytosis by CR3/MAC-1 and SRAI/II was further inhibited by PI3K inhibitors wortmannin and LY-294002 and PLCgamma inhibitor U-73122 [22].

Other interactions of Msr1

• In this study, Apoe-/- mice lacking SR-A or CD36, backcrossed into the C57BL/6 strain for 7 generations, were fed an atherogenic diet for 8 weeks [13].
• Disparate regulation and function of the class A scavenger receptors SR-AI/II and MARCO [9].
• After 4 or 12 weeks of a high-fat diet, the sizes of atherosclerotic lesions in MSR-A/LDLR double knockout mice were significantly reduced (p < 0.05) compared with those in LDLR single knockout mice [23].
• It also suppressed expression of the 2 major scavenger receptors (scavenger receptor-A [SR-A] and CD36), in part by inhibiting IL-6, and inhibited macrophage foam cell formation [24].
• The macrophage class A scavenger receptors, macrophage receptor with a collagenous structure (MARCO) and type I/II class A scavenger receptor (SR-AI/II), share structural features and roles in host defense, but little is known about their regulation and signaling properties [9].

Analytical, diagnostic and therapeutic context of Msr1

• Immunoprecipitation from macrophages and stably transfected Chinese hamster ovary cells revealed that the antigen recognized by monoclonal 2F8 is identical to murine macrophage scavenger receptor [25].
• Electron microscopy revealed that most L. monocytogenes had been eliminated from the lysosomes of MSR-A+/+ macrophages in vivo and in vitro [26].
• 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 [27].
• Reverse transcription-polymerase chain reaction (RT-PCR) analysis and scavenger receptor Type A (SRA) knock-out mice were used to assess the role of these receptors in mediating immune responses [28].
• Similarly, 2F8 detected SR-A protein in MPM by Western blotting in all strains except C57BL/6 [29].

References