IL-22 Mediates Host Defense against an Intestinal Intracellular Parasite in the Absence of IFN-γ at the Cost of Th17-Driven Immunopathology

Abstract

The roles of Th1 and Th17 responses as mediators of host protection and pathology in the intestine are the subjects of intense research. In this study, we investigated a model of intestinal inflammation driven by the intracellular apicomplexan parasite Eimeria falciformis. Although IFN-γ was the predominant cytokine during E. falciformis infection in wild-type mice, it was found to be dispensable for host defense and the development of intestinal inflammation. E. falciformis-infected IFN-γR−/− and IFN-γ−/− mice developed dramatically exacerbated body weight loss and intestinal pathology, but they surprisingly harbored fewer parasites. This was associated with a striking increase in parasite-specific IL-17A and IL-22 production in the mesenteric lymph nodes and intestine. CD4+ T cells were found to be the source of IL-17A and IL-22, which drove the recruitment of neutrophils and increased tissue expression of anti-microbial peptides (RegIIIβ, RegIIIγ) and matrix metalloproteinase 9. Concurrent neutralization of IL-17A and IL-22 in E. falciformis-infected IFN-γR−/− mice resulted in a reduction in infection-induced body weight loss and inflammation and significantly increased parasite shedding. In contrast, neutralization of IL-22 alone was sufficient to increase parasite burden, but it had no effect on body weight loss. Treatment of an E. falciformis-infected intestinal epithelial cell line with IFN-γ, IL-17A, or IL-22 significantly reduced parasite development in vitro. Taken together, to our knowledge these data demonstrate for the first time an antiparasite effect of IL-22 during an intestinal infection, and they suggest that IL-17A and IL-22 have redundant roles in driving intestinal pathology in the absence of IFN-γ signaling.

Cytotoxic effector functions of T cells are not required for protective immunity against fatal Rickettsia typhi infection in a murine model of infection: Role of TH1 and TH17 cytokines in protection and pathology

“…Finally, treatment of epithelial cells infected with the intracellular apicomplexan parasite Eimeria ( E .) falciformis with either IFNγ, IL-22 or IL-17A reduces parasite growth in vitro [77]. Moreover, C57BL/6 IFNγR -/- as well as C57BL/6 IFNγ -/- mice infected with this parasite showed higher pathology and body weight loss but reduced pathogen burden compared to wild-type mice [77], demonstrating that IFNγ is dispensable for the elimination of this pathogen.…”

T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

“…In the gut, IL-22 was found to restrict commensal bacteria to their tissue niches, thereby preventing inflammation and providing protection from chronic inflammatory and autoimmune diseases 155–157 . In the liver, IL-22 expressing Th cells were found to protect hepatocytes during acute liver inflammation 158 .…”

Interleukin-22 Reduces Lung Inflammation during Influenza A Virus Infection and Protects against Secondary Bacterial Infection

“…Of importance, IL-22 can provide protective innate immunity when the adaptive immune system is impaired. This redundant function has been described during infection with C. albicans and Eimeria falciformis (38)(39)(40). Finally, a deleterious role for IL-22 on intestinal inflammation was reported after oral infection with Toxoplasma gondii (37,41).…”