Homeostatic Regulation of Salmonella-Induced Mucosal Inflammation and Injury by IL-23

Abstract

IL-12 and IL-23 regulate innate and adaptive immunity to microbial pathogens through influencing the expression of IFN-γ, IL-17, and IL-22. Herein we define the roles of IL-12 and IL-23 in regulating host resistance and intestinal inflammation during acute Salmonella infection. We find that IL-23 alone is dispensable for protection against systemic spread of bacteria, but synergizes with IL-12 for optimal protection. IL-12 promotes the production of IFN-γ by NK cells, which is required for resistance against Salmonella and also for induction of intestinal inflammation and epithelial injury. In contrast, IL-23 controls the severity of inflammation by inhibiting IL-12A expression, reducing IFN-γ and preventing excessive mucosal injury. Our studies demonstrate that IL-23 is a homeostatic regulator of IL-12-dependent, IFN-γ-mediated intestinal inflammation.

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

“…Furthermore, neutrophil depletion resulted in a significant blunting of mucosal Ifng expression in the cecal mucosa 2 days after S. Typhimurium infection. Consistent with the important role of IFN-␥ in driving inflammatory changes in tissue (7,8), the severity of histopathological lesions in the cecal mucosa was significantly reduced in S. Typhimurium-infected neutrophil-depleted mice. A marked reduction in the severity of histopathological changes in response to S. Typhimurium infection is also observed in ligated ileal loops of calves with CD18 deficiency, a primary immunodeficiency resulting in an inability to recruit neutrophils into the intestinal mucosa because CD18/CD11B (CR3) is required for neutrophil extravasation (24).…”

“…IFN-␥ is an important driver of inflammation during S. Typhimurium colitis (7,8). Depletion of a cell type contributing to mucosal IFN-␥ production would thus be expected to reduce the severity of histopathological lesions induced during S. Typhimurium infection.…”

“…A histopathological hallmark of S. Typhimurium-induced gastroenteritis is a severe acute infiltrate of neutrophils in the ileal and colonic mucosae (5, 6). Studies using a mouse model of S. Typhimurium-induced colitis show that in animals lacking IFN-␥, the severity of intestinal inflammation is markedly attenuated (7,8).Conventional wisdom holds that IFN-␥ is produced during the innate phase of a bacterial infection by natural killer (NK) cells and NKT cells (reviewed in reference 9) while CD4 ϩ and CD8 ϩ T cells become the principal cellular sources at later stages, which are governed by adaptive immune responses (reviewed in references 10 and 11). Consistent with this idea, splenic NK cells are a prominent cellular source of innate IFN-␥ production in models of systemic S. Typhimurium infection (12-14).…”

“…A histopathological hallmark of S. Typhimurium-induced gastroenteritis is a severe acute infiltrate of neutrophils in the ileal and colonic mucosae (5, 6). Studies using a mouse model of S. Typhimurium-induced colitis show that in animals lacking IFN-␥, the severity of intestinal inflammation is markedly attenuated (7,8).…”

Innate lymphoid cells regulate intestinal epithelial cell glycosylation

“…6, A and B). Previous reports have shown that expression of IL-22 in ILCs is much higher in mice infected with S. typhimurium (43, 44). Therefore, S. typhimurium –induced epithelial fucosylation may be mediated by ILC3.…”