Atg7 suppresses inflammatory responses in Klebsiella pneumoniae-infected mice by regulating the p38/IκB/NF-κB circuit (IRM9P.720)

Klebsiella pneumoniae (Kp) is a Gram-negative bacterium that can cause serious infections in humans, particularly invading lungs and intestines. Autophagy-related gene 7 (Atg7) has been shown to be associated with certain bacterial infections; however, the role of Atg7 in host immunity against Kp infection has not been elucidated. Here we showed that Atg7 expression was significantly increased in murine alveolar macrophage (MH-S) cells upon Kp infection, whereas knocking down Atg7 with siRNA increased bacterial burdens in MH-S cells. In addition, using biochemical assays and whole animal imaging analysis, we found that compared to WT mice atg7 knockout (KO) mice exhibited increased susceptibility to Kp infection, with decreased survival rates, increased bacterial burdens, and enhanced lung injury. Moreover, atg7 KO mice induced proinflammatory cytokines and superoxide production in Kp-infected lungs. Similarly, Atg7 silencing in MH-S cells markedly increased levels of cytokines. Mechanistically, we observed that Atg7 depletion regulated p38 phosphorylation which changed IκB binding and inhibited NF-κB nuclear translocation, thus exacerbating NF-κB-mediated cytokine secretion. Collectively, these findings indicate that Atg7 offers resistance to Kp infection by modulating both systemic and local production of proinflammatory cytokines via a p38IκB/NF-κB pathway.