title: The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia.
abstract: Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti-inflammatory IL-10 by lung CD11b+Ly6GintLy6CloF4/80+cells. Cardiolipin induces PPARγ SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy.
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chakraborty
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.|Department of Immunology, 200 Lothrop St, University of Pittsburgh School of Medicine, E1040 BSTWR, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Raundhal
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Morse
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh School of Medicine, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Oriss
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Huff
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, 3500 Terrace St, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, 3500 Terrace St, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Watkins
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, 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 School of Medicine, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.|Department of Immunology, 200 Lothrop St, University of Pittsburgh School of Medicine, E1040 BSTWR, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.|Department of Immunology, 200 Lothrop St, University of Pittsburgh School of Medicine, E1040 BSTWR, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007710:Klebsiella Infections / Q000382:microbiology / Q000503:physiopathology*; D007711:Klebsiella pneumoniae / Q000302:isolation & purification*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D000067996:RAW 264.7 Cells; D058207:Sumoylation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D002308:Cardiolipins; D056572:Histone Deacetylase Inhibitors; D008070:Lipopolysaccharides; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10