IL-22 Restrains Tapeworm-Mediated Protection against Experimental Colitis via Regulation of IL-25 Expression

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.

Triggering immunological memory against the tapeworm Hymenolepis diminuta to protect against colitis

“…Corroborating previous data, Hd Ag alone suppressed DNBS‐induced colitis with a threshold dose of ~500 μg (ip.) and was most effective with repeated dosing . We extend these findings, demonstrating subcutaneous, but not intramuscular, administration could block colitis.…”

“…and was most effective with repeated dosing. 14,17,32 We extend these findings, demonstrating subcutaneous, but not intramuscular, administration could block colitis. It is also noteworthy that repeated doses of Trichuris suis were used in the preliminary trails in IBD.…”

“…We have reported that daily (or repeated) doses of Hd Ag (1 mg, ip.) ameliorated the severity of DNBS and dextran‐sodium sulphate‐induced colitis . Using a memory protocol where mice are infected 28 days prior to the co‐treatment with a single 1 mg dose of Hd Ag and then DNBS (ir.…”

“…Thus, the questions arises, in a system in which primary infection blocks disease, is the response more rapid with a secondary infection and, more pertinently, can protection be triggered in previously infected mice with helminth antigen. Prior to addressing this issue in the H. diminuta ‐DNBS murine colitis model, there was an additional challenge—a crude extract of the worm is anticolitic in naïve mice: a finding not unlike that from Dwindell et al who reported that extracts of H. diminuta evoked changes in myoelectrical activity in the small intestine of naïve rats.…”

“…ameliorated the severity of DNBS and dextran-sodium sulphate-induced colitis. 14,17 Using a memory protocol where mice are infected 28 days prior to the co-treatment with a single 1 mg dose of HdAg and then DNBS (ir. ), resulted in substantial protection from disease.…”