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

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 (nfkb). 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.