Cardiolipin-mediated PPARγ S112 phosphorylation impairs IL-10 production and inflammation resolution during bacterial pneumonia

Cell Rep. 2021 Feb 9;34(6):108736. doi: 10.1016/j.celrep.2021.108736.


Bacterial pneumonia is a global healthcare burden, and unwarranted inflammation is suggested as an important cause of mortality. Optimum levels of the anti-inflammatory cytokine IL-10 are essential to reduce inflammation and improve survival in pneumonia. Elevated levels of the mitochondrial-DAMP cardiolipin (CL), reported in tracheal aspirates of pneumonia patients, have been shown to block IL-10 production from lung MDSCs. Although CL-mediated K107 SUMOylation of PPARγ has been suggested to impair this IL-10 production, the mechanism remains elusive. We identify PIAS2 to be the specific E3-SUMOligase responsible for this SUMOylation. Moreover, we identify a concomitant CL-mediated PPARγ S112 phosphorylation, mediated by JNK-MAPK, to be essential for PIAS2 recruitment. Furthermore, using a clinically tested peptide inhibitor targeting JNK-MAPK, we blocked these post-translational modifications (PTMs) of PPARγ and rescued IL-10 expression, improving survival in murine pneumonia models. Thus, we explore the mechanism of mito-DAMP-mediated impaired lung inflammation resolution and propose a therapeutic strategy targeting PPARγ PTMs.

Keywords: IL-10; JNK-MAPK; Klebsiella; PPARγ; SUMOylation; acute lung injury; cardiolipin; lung inflammation resolution; mitochondrial-DAMP; pneumonia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiolipins / immunology*
  • Interleukin-10 / immunology*
  • Klebsiella Infections / immunology*
  • Klebsiella Infections / pathology
  • Klebsiella pneumoniae / immunology*
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • PPAR gamma / immunology*
  • Phosphorylation / immunology
  • Pneumonia, Bacterial / immunology*
  • Pneumonia, Bacterial / microbiology
  • Pneumonia, Bacterial / pathology
  • RAW 264.7 Cells


  • Cardiolipins
  • IL10 protein, mouse
  • PPAR gamma
  • Pparg protein, mouse
  • Interleukin-10