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.
Highlights
Bacterial pneumonia is a significant healthcare burden worldwide
We previously showed that CD11b þ Ly6GintLy6CloF4/80 þ cells characterized as lung myeloid-derived suppressor cells (MDSCs)[14,15] have an important function in neutrophil efferocytosis after infection with K. pneumoniae[16]
We previously showed that mice infected with 100 colony-forming units (c.f.u.) of K. pneumoniae have a 100% survival rate while those infected with a higher dose (1,000 c.f.u.) show 50% survival[16]
Summary
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-damageassociated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Cardiolipin induces PPARg 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. Our study identifies cardiolipin as a mediator of non-resolving pneumonia via SUMOylation of PPARg in which HDAC inhibition provides therapeutic benefit
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