Lyn cooperating with lipid rafts regulates inflammatory responses in Klebsiella pneumoniae infection through the p38/NF-κB pathway

摘要

Klebsiella pneumoniae is one of the most common pathogens in nosocomial infections and is becoming increasingly multidrug-resistant. However, the underlying molecular pathogenesis of this bacterium remains elusive, limiting the therapeutic options. Understanding the mechanism of its pathogenesis may facilitate the development of antibacterial therapeutics. Here, we show that Lyn, a pleiotropic Src tyrosine kinase, is involved in host defense against K. pneumoniae (Kp) by regulating phagocytosis process and simultaneously downregulating inflammatory responses. Using acute infection mouse models, we observed that lyn^−/− mice were more susceptible to Kp with increased mortality and severe lung injury compared with wild-type mice. Kp infected-lyn^−/− mice exhibited elevated inflammatory cytokines (IL-6 and TNF-α), and increased superoxide in the lung and other organs. In addition, the phosphorylation of p38 and NF-κB p65 subunit increased markedly in response to Kp infection in lyn^−/− mice. We also demonstrated that the translocation of p65 from cytoplasm to nuclei increased in cultured murine lung epithelial cells by Lyn siRNA knockdown. Furthermore, lipid rafts clustered with activated Lyn and accumulated in the site of Kp invasion. Taken together, these findings revealed that Lyn may participate in host defense against Kp infection through the negative modulation of inflammatory cytokines.