Critical role of Th17 responses in a murine model of Neisseria gonorrhoeae genital infection
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Host immune responses, including the characteristic influx of neutrophils, against Neisseria gonorrhoeae are poorly understood; adaptive immunity is minimal and nonprotective. The importance of the newly defined Th17 cell lineage has become increasingly recognized in inflammatory and autoimmune disease, and in defense against certain infections. Th17 cells secrete IL-17, which binds to its ubiquitous receptor, IL-17RA, and stimulates the release of CXC chemokines, granulocyte colony-stimulating factor, defensins, and other immune effector molecules. Thus IL-17 is involved in the mobilization of neutrophils and other innate defense mechanisms. We hypothesize that N. gonorrhoeae selectively elicits Th17-dependent responses which recruit innate defense mechanisms including neutrophils and antimicrobial proteins that it can resist. To test this hypothesis in vitro, mouse splenic mononuclear cells were stimulated with either whole N. gonorrhoeae cells or their outer membrane vesicles and analyzed using flow cytometry; supernatants were assayed for cytokines by ELISA. IL-17 production was seen in both cases, in addition to other inflammatory cytokines associated with a Th17 response, including IL-6, TNFα, and IL-1β. The Th17-inducing cytokines IL-6 and IL-23 were produced in response to N. gonorrhoeae by mouse bone-marrow derived dendritic cells as well as human macrophage-like cells (THP-1). Using a mouse genital tract infection model to test the whether there is a Th17 response in vivo, mice were infected with N. gonorrhoeae and IL-17 was induced in the iliac lymph nodes of mice during infection. Antibody blockade of IL-17 or deletion of the major IL-17 receptor in IL-17RA-knockout mice led to prolonged infection and diminished neutrophil influx. Another crucial pro-inflammatory cytokine produced by Th17 cells, IL-22, appeared to have an inverse role to IL-17 in vivo, as IL-22 knockout mice showed a decreased duration of infection. Genital tract tissue from IL-17RA-knockout mice showed reduced production of neutrophil-attractant chemokines in response to culture with N. gonorrhoeae. These results imply a crucial role for IL-17 and Th17 cells in the immune response to N. gonorrhoeae.