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Role of macrophage scavenger receptor in endotoxin shock
Y Kobayashi1, C Miyaji, H Watanabe
1Second Department of Pathology, Niigata University School of Medicine, Niigata 951-8510, Japan.
Abstract:
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.
Insights
Macrophage scavenger receptor A (MSR-A) plays a detrimental role in endotoxin shock by increasing interleukin-1 beta production. MSR-A deficiency protects mice from lipopolysaccharide-induced mortality.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Lipopolysaccharide (LPS) stimulates macrophages to release inflammatory mediators via receptors like CD14 and macrophage scavenger receptor class A (MSR-A).
- MSR-A recognizes various anionic ligands, suggesting a role in host defense against bacterial components.
- The precise role of MSR-A in endotoxin shock remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of MSR-A in endotoxin shock using MSR-A-deficient mice.
- To determine how MSR-A influences lipopolysaccharide (LPS) binding, clearance, and subsequent inflammatory responses.
Main Methods:
- Utilized MSR-A-deficient (MSR-A(-/-)) and wild-type (MSR-A(+/+)) mice.
- Assessed LPS binding to peritoneal macrophages.
- Measured LPS clearance from serum after intraperitoneal administration.
- Quantified LPS-induced cytokine expression in the liver and serum, specifically focusing on interleukin-1 beta (IL-1beta).
- Evaluated mortality rates following LPS challenge and the effect of IL-1 receptor antagonist pretreatment.
Main Results:
- Macrophages from MSR-A(-/-) mice exhibited reduced LPS binding compared to wild-type.
- Serum LPS clearance was slower in MSR-A(-/-) mice.
- While overall hepatic cytokine expression was similar, MSR-A(-/-) mice showed lower IL-1beta levels in both expression and serum.
- MSR-A(+/+) mice had higher mortality following high-dose LPS administration, which was reduced by IL-1 receptor antagonist treatment.
Conclusions:
- MSR-A-mediated macrophage activation appears to have a negative role in protecting against endotoxin shock.
- Enhanced IL-1beta production by macrophages, facilitated by MSR-A, contributes to mortality in endotoxin shock.
- Targeting MSR-A or IL-1beta pathways could be a therapeutic strategy for endotoxin shock.