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

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.

Mitochondrial Function in Allergic Disease

“…External cardiolipin can be internalised via PAMP receptors, and within the cell, it promotes proinflammatory cytokine production by directly binding to NLRP3 [33]. It has also been observed to suppress anti-inflammatory signalling by inhibiting the production of IL-10 [34]. Therefore, cardiolipin release can lead to a persistent inflammatory environment, conducive for the development of allergies, asthma and MetS.…”

The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

“…Besides, there are some aspects of MDSCs that have enormous potential in biomedicine. First, these cells were identified during acute disease caused by different strains of Klebsiella pneumoniae . Therefore, these cells could be involved in other acute bacterial and viral infections, as well as in sepsis.…”

“…This treatment allows the generation of CD11b + Ly6C + and CD11b + Ly6G + MDSCs subsets with high suppressive ability mediated by Arg‐1 and iNOS expression . LPS administration to the lungs of mice is a useful alternative methodology to obtain CD11b + GR1 + F4/80 + MDSCs that actively produce IL‐10 and are capable of suppressing the Th 2 cell response …”

The interplay between neutrophils and microbiota in cancer

“…Neutrophils may be a key responder to chemotherapy‐induced damage. Cisplatin treatment is linked to mitochondrial disruption and ROS production, both of which could lead to highly immunogenic NET formation . Furthermore, when the mitochondria is disrupted by chemotherapeutics, it can lead to the activation of FPR1 that is highly expressed on neutrophils and leads to ROS production.…”