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.
- 1. Cardio-Respiratory Disease Biology, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
- 2. Department of Pathology, Sri Ramachandra Medical College and Research Institute, Chennai 600116, India.
- 3. Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
- 4. Cardio-Respiratory Disease Biology, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India. Electronic address: [email protected].
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.