Suppression of TLR4-mediated inflammatory response by macrophage class A scavenger receptor (CD204).

Abstract

The class A scavenger receptor (SR-A, CD204), one of the principal receptors expressed on macrophages, has been found to regulate inflammatory response and attenuate septic endotoxemia. However, the detailed mechanism of this process has not yet been well characterized. To clarify the regulative mechanisms of lipopolysaccharide (LPS)-induced macrophage activation by SR-A, we evaluated the activation of Toll-like receptor 4 (TLR4)-mediated signaling molecules in SR-A-deficient (SR-A(-/-)) macrophages. In a septic shock model, the blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and interferon (IFN)-β were significantly increased in SR-A(-/-) mice compared to wild-type mice, and elevated nuclear factor kappa B (NFκB) activation was detected in SR-A(-/-) macrophages. SR-A deletion increased the production of pro-inflammatory cytokines, and the phosphorylation of mitogen-activated protein kinase (MAPK) and NFκB in vitro. SR-A deletion also promoted the nuclear translocation of NFκB and IFN regulatory factor (IRF)-3. In addition, a competitive binding assay with acetylated low-density lipoprotein, an SR-A-specific ligand, and anti-SR-A antibody induced significant activation of TLR4-mediated signaling molecules in wild-type macrophages but not in SR-A(-/-) macrophages. These results suggest that SR-A suppresses the macrophage activation by inhibiting the binding of LPS to TLR4 in a competitive manner and it plays a pivotal role in the regulation of the LPS-induced inflammatory response.

• Authors: Koji Ohnishi, Yoshihiro Komohara, Yukio Fujiwara, Kenichi Takemura, XiaoFeng Lei, Takenobu Nakagawa, Naomi Sakashita, Motohiro Takeya
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 411 Issue 3 Pg. 516-22 (Aug 05 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21756882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Interferon Regulatory Factor-3
• Irf3 protein, mouse
• Lipopolysaccharides
• Msr1 protein, mouse
• NF-kappa B
• Scavenger Receptors, Class A
• Tlr4 protein, mouse
• Toll-Like Receptor 4

Topics

• Animals
• Cell Nucleus (metabolism)
• Cytokines (biosynthesis)
• Inflammation (genetics, immunology)
• Interferon Regulatory Factor-3 (metabolism)
• Lipopolysaccharides (immunology)
• Macrophage Activation
• Macrophages (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Scavenger Receptors, Class A (genetics, immunology)
• Sequence Deletion
• Shock, Septic (genetics, immunology)
• Toll-Like Receptor 4 (immunology)