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

Molekulare Parasitologie, Humboldt Universität zu Berlin, D-10115 Berlin, Germany.
The Journal of Immunology (Impact Factor: 4.92). 03/2012; 188(5):2410-8. DOI: 10.4049/jimmunol.1102062
Source: PubMed


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.

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Available from: Anja A Kühl, Jan 07, 2015
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    • "multiple pathogen associated molecular patterns (PAMPs) may be responsible for bladder RegIIIγ expression, just as LPS and flagellin regulate RegIIIγ mRNA levels in the gut.[16,45]Alternatively, induction of RegIIIγ mRNA in UPEC infected bladders may occur as consequence of cytokine signaling. In the lung, interleukin-6 (IL-6) leads to phosphorylation of Signal transducer and activator of transcription (Stat) 3, which translocates to the nucleus and mediates RegIIIγ mRNA transcription.[12,51]In the skin of mice and humans with psoriasis, HIP/PAP and RegIIIγ undergo robust mRNA and protein induction under the direction of IL- 17, another cytokine capable of eliciting Stat3 phosphorylation.[11]In the stomach, the Helicobacter pylori CagA protein elicits IL-11 production, which leads to Stat3 phosphorylation and RegIIIγ expression.[52]In the mouse colon, infectious and chemical agents trigger production of IL-22, which induces epithelial RegIIIγ expression.[40,53,54]Altogether, these observations warrant future studies of Stat3 and its upstream regulatory cytokines in the regulation of RegIIIγ during experimental UTI. "
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    • "It has been shown that the modulation toward a Th1 phenotype with upregulation of IFN-γ may ameliorate the severity of the disease, though in most of the cases this is related to the resolution of the infections which did not occur in our study (Falcone et al. 1998; Castilow et al. 2008; Kato et al. 1999; Chen et al 2011). Recently, a study associated the absence of IFN-γ to high levels of enteropathy in Eimeria falciformis infections, but the pathology was mediated by Th17 cytokines (IL-17A and IL-22) generated in the absence of IFN-γ (Stange et al. 2012). Lawrence et al. (1998) showed that enteropathy in Trichinella spiralis-infected mice is exclusively mediated by TNF-α under regulation by IL-4 and Th2. "
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    • "Although Th17 cells have been reported to be the major effector T cells that provide immunity in the intestine [39] against many potential pathogens [40,41], the exact roles of Th17 cells in the intestine are incompletely understood. Studies by Zhang et al. [26] and Stange et al. [29], in addition to our current report, support the notion that IL17A has a role in E. tenella pathogenesis. In summary, the present study confirms and extends previous observations in avian coccidiosis that neutralization of IL17A reduced E. tenella multiplication and diminished tissue lesions on the basis of a herein demonstrated reduction of parasitized epithelial cell motility. "
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