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

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, Rama K. Mallampalli, Valerian E. Kagan, Anuradha Ray and Prabir Ray ()
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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
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
Prabir Ray: Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms13944

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