IL-22BP production is heterogeneously distributed in Crohn’s disease

Abstract

Background & aims: IL-22 binding protein (IL-22BP) is a soluble and specific inhibitor of IL-22, a cytokine with known protective actions on intestinal epithelial cells during inflammation. Although eosinophils and mononuclear phagocytes (MNP) were shown to be the producers of IL-22BP in the intestine lamina propria (LP), it has recently been proposed that CD4+ T cells represent an additional source of IL-22BP in the gut during Crohn's disease (CD). In this study we sought to confirm these findings and to assess IL-22BP secretion levels. Methods: We investigated IL-22BP cellular sources in CD gut samples using qPCR and ELISA on FACS-sorted LP and mesenteric lymph nodes (MLN) cell subsets. We also evaluated IL-22BP levels in ex-vivo culture of intestinal biopsies. Results: MNP (HLA DR+ CD11c+ cells) and eosinophils isolated from LP CD tissues expressed IL22RA2, while the expression measured in the CD4+ and CD8+ T cells fractions was undetectable or 100-1000 times lower than in MNP. In MLN, IL22RA2 expression in T cells was either undetectable of 1000-fold lower than in MNPs without differences between naive and non-naive subsets. IL22RA2 expression was undetectable after ex vivo activation of both CD4+ and CD8+ T cells from LP or MLNs and IL-22BP was not detected in their supernatant, either activated or not. LP eosinophils appeared capable of secreting IL-22BP but not DCs likely due to in vitro activation as confirmed with monocyte-derived DCs. We also identified higher production of IL-22BP from ileum as compared to colon biopsies and demonstrated that IL-22BP levels correlated with those of eotaxins but not with TNF and IL-6. Finally, high ex vivo production of IL-22BP in mucosa biopsies from CD patients was only observed in smokers. Conclusion: We confirmed that eosinophils and MNPs are the major sources of IL-22BP in the gut during CD and found no clear evidence for IL-22BP expression by T cells. This work also provides new insights on factors regulating intestinal IL-22BP levels.