Research ArticleImmunology

Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity

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Science Signaling  22 Sep 2015:
Vol. 8, Issue 395, pp. ra95
DOI: 10.1126/scisignal.aaa6179

Mitochondrial phospholipid modulates immunity

The phospholipid cardiolipin normally resides in the inner mitochondrial membrane; however, cardiolipin becomes exposed on the outer membrane of damaged mitochondria and acts as an “eat me” signal to promote mitochondrial elimination by mitophagy. Balasubramanian et al. showed that cardiolipin presented on vesicular, mitochondrial, or bacterial membranes to macrophages functioned as an eat me signal to the macrophages, through a process dependent on the macrophage scavenger receptor CD36. Independently of phagocytosis, cardiolipin also inhibited macrophage cytokine production in response to the bacterial compound lipopolysaccharide. Together, these results suggest that cardiolipin both promotes the phagocytosis of cellular debris and pathogens and dampens the innate immune response.


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.

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