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The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia

Author

Listed:
  • Krishnendu Chakraborty

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Mahesh Raundhal

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine
    Department of Immunology)

  • Bill B. Chen

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Christina Morse

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Yulia Y. Tyurina

    (Center for Free Radical and Antioxidant Health, University of Pittsburgh School of Medicine)

  • Anupriya Khare

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Timothy B. Oriss

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Rachael Huff

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Janet S. Lee

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Claudette M. St. Croix

    (Center for Biologic Imaging, University of Pittsburgh School of Medicine, 3500 Terrace St)

  • Simon Watkins

    (Center for Biologic Imaging, University of Pittsburgh School of Medicine, 3500 Terrace St)

  • Rama K. Mallampalli

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine)

  • Valerian E. Kagan

    (Center for Free Radical and Antioxidant Health, University of Pittsburgh School of Medicine)

  • Anuradha Ray

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine
    Department of Immunology)

  • Prabir Ray

    (Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine
    Department of Immunology)

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.

Suggested Citation

  • Krishnendu Chakraborty & Mahesh Raundhal & Bill B. Chen & Christina Morse & Yulia Y. Tyurina & Anupriya Khare & Timothy B. Oriss & Rachael Huff & Janet S. Lee & Claudette M. St. Croix & Simon Watkins , 2017. "The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms13944
    DOI: 10.1038/ncomms13944
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