Regulation of respiratory mucosal immunity by epithelial cell secreted antimicrobial molecules (INC5P.330)

Abstract

Abstract The ability of the host to avoid infection depends largely on mechanisms of innate immunity. Several secreted epithelial cell-secreted proteins including MUC5AC, SPLUNC1, SP-A, and LL37 form an antimicrobial milieu to clear inhaled pathogens and to participate in immune response. In this study, we try to determine the underlying mechanisms of pulmonary antimicrobial activity following Pseudomonas aeruginosa infection. Splunc1 KO mice showed accelerated mortality and increased susceptibility to microbial infection with significantly decreased survival rates, increased bacterial burdens, exaggerated tissue injuries, and elevated proinflammatory cytokine levels, compared with those of their wild-type littermates. Increased neutrophil infiltration in Splunc1 KO mice was accompanied by elevated levels of chemokines including Cxcl1, Cxcl2, and Ccl20. Moreover, the expression of several epithelial secretory proteins such as Muc5ac, Muc5b, and CCSP, as well as antimicrobial molecules including LL37, lysozyme, and lactoferrin, was considerably suppressed in the lungs of Splunc1 KO mice. The deficiency of Splunc1 in mouse airway epithelium also resulted in increased biofilm formation. Using in vitro and in vivo approaches, we demonstrated the role of secreted antimicrobial molecules in protecting the host from Pseudomonas-induced respiratory infections and supported the notion that host antimicrobial milieu plays a critical role in determining infectious susceptibility.