Abstract
Interleukin (IL)-22, an immune cell-derived cytokine whose receptor expression is restricted to non-immune cells (e.g. epithelial cells), can be anti-inflammatory and pro-inflammatory. Mice infected with the tapeworm Hymenolepis diminuta are protected from dinitrobenzene sulphonic acid (DNBS)-induced colitis. Here we assessed expulsion of H. diminuta, the concomitant immune response and the outcome of DNBS-induced colitis in wild-type (WT) and IL-22 deficient mice (IL-22-/-) ± infection. Interleukin-22-/- mice had a mildly impaired ability to expel the worm and this correlated with reduced or delayed induction of TH2 immunity as measured by splenic and mesenteric lymph node production of IL-4, IL-5 and IL-13 and intestinal Muc-2 mRNA and goblet cell hyperplasia; in contrast, IL-25 increased in the small intestine of IL-22-/- mice 8 and 12 days post-infection compared to WT mice. In vitro experiments revealed that H. diminuta directly evoked epithelial production of IL-25 that was inhibited by recombinant IL-22. Also, IL-10 and markers of regulatory T cells were increased in IL-22-/- mice that displayed less DNBS (3 mg, ir. 72h)-induced colitis. Wild-type mice infected with H. diminuta were protected from colitis, as were infected IL-22-/- mice and the latter to a degree that they were almost indistinguishable from control, non-DNBS treated mice. Finally, treatment with anti-IL-25 antibodies exaggerated DNBS-induced colitis in IL-22-/- mice and blocked the anti-colitic effect of infection with H. diminuta. Thus, IL-22 is identified as an endogenous brake on helminth-elicited TH2 immunity, reducing the efficacy of expulsion of H. diminuta and limiting the effectiveness of the anti-colitic events mobilized following infection with H. diminuta in a non-permissive host.
Highlights
Interleukin (IL)-22, a member of the IL-10 family, is produced predominantly by innate (NK cells (NK22), γδ T cells, innate lymphoid cells type 3 (ILC3s) and adaptive (CD4+ Th22 and Th17, CD8+ T cells) immune cells: a non-immune source of IL-22 has not been described
Worm burden and granuloma size is not different in schistosoma-infected WT and IL-22-/- mice [15], whereas IL-22 was important in the goblet cell hyperplasia and mucin secretion response following infection with the intestinal nematodes, Trichuris muris and Nippostrongylus brasiliensis [20]
IL-22-/- mice displayed a slight delay in the kinetics of expulsion of H. diminuta: only 22% (2/9 mice) of infected IL-22-/- mice had expelled H. diminuta by 8 days post-infection compared to 55% (5/9 mice) of WT mice (Fig 1); at this time-point 33% of infected IL-22-/- mice harboured 3 or 4 worms, burdens not observed in WT mice
Summary
Interleukin (IL)-22, a member of the IL-10 family, is produced predominantly by innate (NK cells (NK22), γδ T cells, innate lymphoid cells type 3 (ILC3s) and adaptive (CD4+ Th22 and Th17, CD8+ T cells) immune cells: a non-immune source of IL-22 has not been described. The heterodimeric IL-22 receptor consists of the IL-10R2 subunit and the unique IL-22R1 subunit, and is restricted to non-hematopoetic cells (e.g. hepatocytes and epithelium of the gastrointestinal tract) [1]. Data from studies of the gastrointestinal tract suggest that the role of IL-22 is contextual, with beneficial or detrimental affects depending on the nature of the disease or immune activity being assessed. Local delivery of the IL-22 gene attenuated the spontaneous colitis that develops in T cell receptor (TCR)-α knockout (KO) mice [6] and that evoked by transfer of naïve CD45RBhi T cells into RAG2-/- mice [4]. Fewer IL-22+ cells have been described in inflamed tissue from patients with ulcerative colitis compared to healthy individuals [8]. ILC3 from patients with mild-moderate ulcerative colitis were reported to have increased IL-22 production [9]
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