title: Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity.
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.
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. kris.balasub@gmail.com bengt.fadeel@ki.se kagan@pitt.edu.
authors.forename: Krishnakumar
authors.initials: K
authors.lastname: Balasubramanian
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Dariush
authors.initials: D
authors.lastname: Mohammadyani
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Haider Hussain
authors.initials: HH
authors.lastname: Dar
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Jian Fei
authors.initials: JF
authors.lastname: Jiang
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Watkins
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tyurin
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Katharina
authors.initials: K
authors.lastname: Klöditz
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Anastassia
authors.initials: A
authors.lastname: Polimova
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Valentyna I
authors.initials: VI
authors.lastname: Kapralova
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
authors.affiliation: Division of Metabolic and Vascular Health, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Klein-Seetharaman
authors.affiliation: Department of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA. Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15215, USA.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayir
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden. kris.balasub@gmail.com bengt.fadeel@ki.se kagan@pitt.edu.
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. kris.balasub@gmail.com bengt.fadeel@ki.se kagan@pitt.edu.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
mesh_terms: D018955:CD36 Antigens / Q000276:immunology*; D002308:Cardiolipins / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D010587:Phagocytosis; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D018955:CD36 Antigens; D002308:Cardiolipins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4