TY - JOUR
T1 - The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia
AU - Chakraborty, Krishnendu
AU - Raundhal, Mahesh
AU - Chen, Bill B.
AU - Morse, Christina
AU - Tyurina, Yulia Y.
AU - Khare, Anupriya
AU - Oriss, Timothy B.
AU - Huff, Rachael
AU - Lee, Janet S.
AU - Croix, St Claudette M.
AU - Watkins, Simon
AU - Mallampalli, Rama K.
AU - Kagan, Valerian E.
AU - Ray, Anuradha
AU - Ray, Prabir
PY - 2017/1/11
Y1 - 2017/1/11
N2 - 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+ Ly6G int Ly6C lo F4/80+ cells. Cardiolipin induces PPAR 3 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.
AB - 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+ Ly6G int Ly6C lo F4/80+ cells. Cardiolipin induces PPAR 3 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.
UR - http://www.scopus.com/inward/record.url?scp=85009250614&partnerID=8YFLogxK
U2 - 10.1038/ncomms13944
DO - 10.1038/ncomms13944
M3 - Article
C2 - 28074841
AN - SCOPUS:85009250614
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 13944
ER -