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

• Published in: Biochemical and biophysical research communications 2011-08, Vol.411 (3), p.516-522
• Main Authors: Ohnishi, Koji, Komohara, Yoshihiro, Fujiwara, Yukio, Takemura, Kenichi, Lei, XiaoFeng, Nakagawa, Takenobu, Sakashita, Naomi, Takeya, Motohiro
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animal models; Animals; ANTIBODIES; BLOOD; Cell Nucleus - metabolism; Cytokines - biosynthesis; IN VITRO; INFLAMMATION; Inflammation - genetics; Inflammation - immunology; INTERFERON; Interferon Regulatory Factor-3 - metabolism; LIGANDS; Lipopolysaccharides - immunology; LIPOPROTEINS; LPS; Macrophage Activation; MACROPHAGES; Macrophages - immunology; Male; MICE; Mice, Inbred C57BL; NF-kappa B - metabolism; PHOSPHORYLATION; RECEPTORS; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - immunology; Septic shock; Sequence Deletion; Shock, Septic - genetics; Shock, Septic - immunology; SR-A; TLR4; Toll-Like Receptor 4 - immunology; TRANSLOCATION
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2011.06.161

► We focused on the interaction between SR-A and TLR4 signaling in this study. ► SR-A deletion promoted NFκB activation in macrophages in septic model mouse. ► SR-A suppresses both MyD88-dependent and -independent TLR4 signaling in vitro. ► SR-A clears LPS binding to TLR4 which resulting in the suppression of TLR4 signals. 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.