IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine

Abstract

Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer (CRC)1. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. IL-22, a cytokine of the IL-10 superfamily, plays an important role for colonic epithelial cell repair, and is increased in the blood and intestine of IBD patients2, 3. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, IL-22RA2), however the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown4, 5. We describe herein that IL-22BP plays a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells (DC) in the colon in steady state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent down regulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumor development if uncontrolled during the recovery phase.Thus the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

Epithelial NAIPs protect against colonic tumorigenesis

“…IL-22bp mRNA was shown to be negatively regulated during DSS colitis in a time-dependent manner and also after biopsy-induced damage. In the biopsy model, this regulation was absent in NLRP3 and NLRP6 inflammasomedeficient mice (Huber et al, 2012). We observed no change in IL-22BP in DSS exposed animals, with no difference between genotypes (Fig.…”

“…4 I). This is in contrast to Huber et al (2012); however, the DSS dosing and timing, and line susceptibility, may affect the timing of IL-22BP protein and mRNA regulation. This data indicates that inflammasomes other than NAIP/NLRC4 are activated during acute colitis, but neither IL-18 and IL-1, nor IL-22 BP levels, play a role in the Naip1-6 / phenotype.…”

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

“…The levels of IL22 in colon are controlled by IL22bp, a high-affinity soluble receptor downregulated in the intestine following tissue damage (45). Accordingly, persistent inflammation and incomplete repair of tissue damage occurring in Kit W-sh mice after DSS withdrawal were associated with higher Il22 and lower Il22bp gene expression than in the WT counterpart.…”

Interleukine 22

“…D'autre part, les effets de l'IL-22 peuvent être neutralisés in vivo grâce à l'expression de son récepteur soluble, l'IL-22 binding protein (IL-22BP). L'IL-22BP est exprimée dans les poumons, la peau, la rate et le côlon [11] [12]. Ces observations ajoutent un niveau de complexité supplémen-taire dans la régulation fonctionnelle de l'IL-22 et pourraient rendre compte des résultats divergents rapportés dans les modèles de greffe allogénique de cellules hématopoïétiques et d'inflammation.…”

“…Ces observations ajoutent un niveau de complexité supplémen-taire dans la régulation fonctionnelle de l'IL-22 et pourraient rendre compte des résultats divergents rapportés dans les modèles de greffe allogénique de cellules hématopoïétiques et d'inflammation. L'expression de l'IL-22BP est régulée via l'IL-18 et l'inflammasome [12]. La participation de l'IL-22BP reste à explorer dans le contexte de GVHD.…”