Tumor Necrosis Factor-α Is Required for Mast Cell-Mediated Host Immunity Against Cutaneous Staphylococcus aureus Infection

Background. Mast cells (MCs) play a key role in immune process response to invading pathogens. Methods. This study assessed the involvement of MCs in controlling Staphylococcus aureus infection in a cutaneous infection model of MC-deficient (Kit(W-sh/W-sh)) mice. Results. KitW-sh/W-sh mice developed significantly larger skin lesions after the cutaneous S. aureus challenge, when compared to wild-type (WT) mice, while MC dysfunction reduced the inflammation response to S. aureus. The levels of tumor necrosis factor (TNF)-alpha in skin tissues were significantly decreased in Kit(W-sh/W-sh) mice upon infection. Moreover, the exogenous administration of MCs or recombinant TNF-alpha effectively restored the immune response against S. aureus in Kit(W-sh/W-sh) mice via the recruitment of neutrophils to the infected site. These results indicate that the effects of MC deficiency are largely attributed to the decrease in production of TNF-alpha in cutaneous S. aureus infection. In addition, S. aureus-induced MC activation was dependent on the c-kit receptor-activated phosphoinositide 3-kinase (PI3K)/AKT/P65-nuclear factor (NF-kappa B) pathway, which was confirmed by treatment with Masitinib (a c-kit receptor inhibitor), Wortmannin (a PI3K inhibitor), and pyrrolidine dithiocarbamate (a NF-kappa B inhibitor), respectively. Conclusions. The present study identifies the critical role of MCs in the host defense against S. aureus infection.