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

Krishnakumar Balasubramanian, Akihiro Maeda, Janet S. Lee, Dariush Mohammadyani, Haider Hussain Dar, Jian Fei Jiang, Claudette M.St Croix, Simon Watkins, Vladimir A. Tyurin, Yulia Y. Tyurina, Katharina Klöditz, Anastassia Polimova, Valentyna I. Kapralova, Zeyu Xiong, Prabir Ray, Judith Klein-Seetharaman, Rama K. Mallampalli, Hülya Bayir, Bengt Fadeel, Valerian E. Kagan

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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.

Original languageEnglish (US)
Article numberra95
JournalScience Signaling
Volume8
Issue number395
DOIs
StatePublished - Sep 22 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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