Sci Signal

Abstract

Among the distinct molecular signatures present in the mitochondrion is the tetra-acylated anionic phospholipid cardiolipin, a lipid also present in primordial, single-cell bacterial ancestors of mitochondria and multiple bacterial species today. Cardiolipin is normally localized to the inner mitochondrial membrane; however, when cardiolipin becomes externalized to the surface of dysregulated mitochondria, it promotes inflammasome activation and stimulates the elimination of damaged or nonfunctional mitochondria by mitophagy. Given the immunogenicity of mitochondrial and bacterial membranes that are released during sterile and pathogen-induced trauma, we hypothesized that cardiolipins might function as "eat me" signals for professional phagocytes. In experiments with macrophage cell lines and primary macrophages, we found that membranes with mitochondrial or bacterial cardiolipins on their surface were engulfed through phagocytosis, which depended on the scavenger receptor CD36. Distinct from this process, the copresentation of cardiolipin with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide dampened TLR4-stimulated production of cytokines. These data suggest that externalized, extracellular cardiolipins play a dual role in host-host and host-pathogen interactions by promoting phagocytosis and attenuating inflammatory immune responses.CA165065/CA/NCI NIH HHS/United StatesES020693/ES/NIEHS NIH HHS/United StatesHL086884/HL/NHLBI NIH HHS/United StatesNS061817/NS/NINDS NIH HHS/United StatesNS076511/NS/NINDS NIH HHS/United StatesOH008282/OH/NIOSH CDC HHS/United StatesP01 HL114453/HL/NHLBI NIH HHS/United StatesP01 HL114453/HL/NHLBI NIH HHS/United StatesP30CA047904/CA/NCI NIH HHS/United StatesR01 HL086884/HL/NHLBI NIH HHS/United StatesU19AIO68021/PHS HHS/United States2016-02-19T00:00:00Z26396268PMC476070