title: 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.
authors.affiliation: Molekulare Parasitologie, Humboldt Universität zu Berlin, D-10115 Berlin, Germany. joerg.stange@hu-berlin.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Stange
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hepworth
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rausch
authors.forename: Lara
authors.initials: L
authors.lastname: Zajic
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.forename: Catherine
authors.initials: C
authors.lastname: Uyttenhove
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Susanne
authors.initials: S
authors.lastname: Hartmann
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
mesh_terms: D000818:Animals; D002432:Cecum / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D002460:Cell Line; D003048:Coccidiosis / Q000276:immunology / Q000401:mortality / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D004539:Eimeria / Q000254:growth & development / Q000276:immunology; D005260:Female; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics; D007378:Interleukins / Q000502:physiology*; D007411:Intestinal Diseases, Parasitic / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D000096743:Interferon gamma Receptor; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D007378:Interleukins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; D000097043:Interleukin-22