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

• Published in: The Journal of immunology (1950) Vol. 188; no. 5; pp. 2410 - 2418
• Main Authors: Stange, Jörg, Hepworth, Matthew R, Rausch, Sebastian, Zajic, Lara, Kühl, Anja A, Uyttenhove, Catherine, Renauld, Jean-Christophe, Hartmann, Susanne, Lucius, Richard
• Format: Journal Article
• Language: English
• Published: United States 01.03.2012
• Subjects: Animals; Cecum - immunology; Cecum - parasitology; Cecum - pathology; Cell Line; Coccidiosis - immunology; Coccidiosis - mortality; Coccidiosis - pathology; Colon - immunology; Colon - parasitology; Colon - pathology; Eimeria - growth & development; Eimeria - immunology; Eimeria falciformis; Female; Immunity, Cellular - genetics; Interferon gamma Receptor; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interleukin-22; Interleukins - physiology; Intestinal Diseases, Parasitic - immunology; Intestinal Diseases, Parasitic - mortality; Intestinal Diseases, Parasitic - pathology; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intracellular Fluid - immunology; Intracellular Fluid - metabolism; Intracellular Fluid - parasitology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Interferon - deficiency; Receptors, Interferon - genetics; Signal Transduction - genetics; Signal Transduction - immunology; Th17 Cells - immunology; Th17 Cells - parasitology; Th17 Cells - pathology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1102062

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.