Abstract 539: Soluble Oxidized Apolipoprotein A-I, a Precursor of Amyloid Fibrils, Activates Secretion of Inflammatory Cytokines in Macrophages

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Atherosclerosis is often described as an inflammatory disease of the arteries. One mechanism whereby apolipoprotein A-I (apoA-I) exerts its anti-atherosclerotic effect is by mitigating the inflammatory response of cells involved in atherosclerosis progression. However, oxidation transforms apoA-I from an anti-inflammatory to a pro-inflammatory protein. We previously reported that oxidation can also promote apoA-I aggregation and formation of amyloid fibrils. In this study, we investigated the mechanistic interplay between oxidation, amyloid formation and the inflammatory response of macrophages to apoA-I. We hypothesized that amyloid fibrils constituted of oxidized apoA-I activate production of inflammatory cytokines in macrophages. To test this hypothesis, amyloidogenic apoA-I was generated by oxidation with an excess of H 2 O 2 (H 2 O 2 -ApoA-I). Intracellular and secreted levels of IL-1β were determined upon incubation of mouse bone marrow derived macrophages (BMDM) with intact-apoA-I, soluble H 2 O 2 -ApoA-I and pre-formed H 2 O 2 -ApoA-I amyloid fibrils. Cellular cholesterol release from RAW264.7 cells was also measured. Soluble H 2 O 2 -ApoA-I (amyloid precursor) retained the cellular cholesterol release capacity of intact-ApoA-I. In BMDM incubated with soluble H 2 O 2 -ApoA-I however, levels of IL-1β synthesis and secretion were at least 2-fold higher than those induced by intact-ApoA-I. In contrast, incubation with H 2 O 2 -ApoA-I amyloid fibrils did not increase the levels of IL-1β synthesis and secretion, compared to intact-ApoA-I. Thus, soluble and functional oxidized apoA-I activates inflammatory cytokine synthesis and secretion in macrophages. Notably, this pro-inflammatory potential was completely neutralized when oxidized apoA-I was aggregated in amyloids. Therefore in atherosclerotic lesions, amyloid formation could reduce, rather than exacerbate, the inflammatory burden produced by pro-inflammatory soluble oxidized apoA-I species.