Abstract 16: Amyloidogenic Modifications of Apolipoprotein A-I Promote a Strong Pro-inflammatory Response in Macrophages, but Formation of Amyloid Fibrils Abrogates the Pro-inflammatory Effect

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Inflammation is central to atherosclerosis, as inactivation of inflammation pathways strongly reduces atherosclerosis progression. Particulate matter, such as cholesterol crystals and amyloid materials, promotes release of the potent pro-inflammatory cytokine IL-1β in macrophages. Recently, it has been demonstrated that soluble substances that are precursors of particulate matter, such as free cholesterol, oxidized LDL and amyloidogenic peptides (i.e. amyloid-β, IAPP), can also induce an inflammatory response. In this study, we investigated the interplay between oxidation of apolipoprotein A-I (apoA-I), amyloid formation, and the inflammatory response of macrophages. We previously reported that oxidation of apoA-I methionines (MetO-ApoA-I) promotes protein aggregation and formation of amyloid fibrils when MetO-ApoA-I is incubated at pH 6.0. In contrast, at physiological pH, MetO-ApoA-I remains soluble and perfectly functional, as it promotes cholesterol efflux from macrophages with the same efficiency of intact-ApoA-I. However, upon incubation of mouse bone marrow derived macrophages with soluble pre-fibrillar MetO-ApoA-I, levels of pro-IL-1β synthesis were more than 2-fold higher than those induced by intact-ApoA-I. In contrast, amyloid fibrils produced by MetO-ApoA-I did not increase the levels of pro-IL-1β synthesis compared to intact-ApoA-I. Furthermore, the pro-inflammatory effect was not observed in macrophages derived from MyD88/TRIF knock-out mice, indicating that the response is membrane TLR receptors-dependent. In contrast, the >2-fold increase (MetO-ApoA-I vs. intact-apoA-I) in pro-IL-1β synthesis was maintained in macrophages derived from CD36 knock-out mice. This observation suggests that the signaling pathway is not exclusively dependent on the TLR2/TLR6/CD36 membrane complex. Thus, in atherosclerotic lesions, oxidized apoA-I species that are amyloidogenic, but otherwise functional, may induce a pro-inflammatory response in macrophages. Amyloid fibril formation in contrast, could reduce, rather than exacerbate, the inflammatory burden produced by these pro-inflammatory apoA-I species by sequestering them in the form of inert amyloids.

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