Apolipoprotein A-I inhibits CD40 proinflammatory signaling via ATP-binding cassette transporter A1-mediated modulation of lipid raft in macrophages

Kai Yin, Wu-Jun Chen, Zhi-Gang Zhou, Guo-Jun Zhao, Yun-Chen Lv, Xin-Pin Ouyang, Xiao-Hua Yu, Yuchang Fu, Zhi-Sheng Jiang, Chao-Ke Tang
Journal of Atherosclerosis and Thrombosis 2012, 19 (9): 823-36

AIM: Apolipoprotein A-I (apoA-I), the major component of high-density lipoprotein (HDL), has been recently found to suppress inflammation. This study was to investigate the effects and potential mechanisms of apoA-I on the CD40/CD40 ligand (CD40L) proinflammatory signaling pathway.

METHODS: Human THP-1 macrophage-derived foam cells were treated with sCD40L alone or in the presence of apoA-I. Secretion of proinflammatory cytokines was performed by enzyme-linked immunosorbent assay(ELISA). The proteins and mRNA expression were examined by western-blot and real-time PCR analysis, respectly. Cholesterol efflux was assessed by liquid scintillation counting. Cholesterol depletion of macrophages was performed with methylated β-cyclodextrin.

RESULTS: ApoA-I inhibits the inflammatory response stimulated by soluble CD40L (sCD40L) in macrophages. In addition, apoA-I inhibited the sCD40L-stimulated activation of nuclear factor-kB (NF-kB). The apoA-I-induced NF-kB deactivation was related to the decreased recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF-6), a crucial adapter protein for CD40 in macrophages, to lipid rafts after being treated by sCD40L. When interfering the expression of ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter for apoA-I in macrophages, it could significantly diminish the effect of apoA-I on the sCD40L-stimulated inflammatory response.

CONCLUSION: ApoA-I suppresses CD40 proinflammatory signaling in macrophages by preventing TRAF-6 translocation to lipid rafts through ABCA1-dependent regulation of free cholesterol (FC) efflux, which may present a novel mechanism of apoA-I-mediated inflammation inhibition in macrophages.

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