T helper type 17 pathway suppression by appendicitis and appendectomy protects against colitis

Abstract

SummaryAppendicitis followed by appendectomy (AA) at a young age protects against inflammatory bowel disease (IBD). We wanted to characterize the role of the T helper type 17 (Th17) system involved in this protective effect. AA was performed on 5-week-old male BALB/c mice and distal-colon samples were harvested. Mice with two laparotomies each served as sham-sham (SS) controls. RNA was extracted from four individual colonic samples per group (AA and SS groups) and each sample microarray-analysed and reverse transcriptionpolymerase chain reaction (RT-PCR)-validated. Gene-set enrichment analysis (GSEA) showed that the Th17 recruitment factor gene CCL20 was significantly suppressed at both 3 days post-AA and 28 days post-AA. Although Th17 cell development differentiation factor genes TGF-β2 and TGF-β3 were significantly up-regulated 3 days post-AA, GSEA 28 days post-AA showed that AA down-regulated 29 gene-sets associated with TGF-β1, TGF-β2 and TGF-β3 in contrast to none up-regulated with any of these genes. GSEA showed substantial down-regulation of gene-sets associated with Th17 lymphocyte recruitment, differentiation, activation and cytokine expression in the AA group 28 days post-AA. We conclude that Th17-system cytokines are kept under control by AA via down-regulation of proinflammatory CCL20, a rapid down-regulation of pro-Th17 cell differentiation genes TGF-β2 and TGF-β3, suppression of RORC-associated genesets, increased protective STAT1 expression and suppression of 81 'pro-Th17' system gene-sets. AA suppresses the Th17 pathway leading to colitis amelioration. Further characterization of Th17-associated genes and biological pathways will assist in the development of better therapeutic approaches in IBD management.

Integrative analysis of Paneth cell proteomic and transcriptomic data from intestinal organoids reveals functional processes dependent on autophagy

“…The Paneth cell-enriched organoids we derived from the Atg16l1 △ IEC mouse model could be perceived as a biased representation of the role autophagy impairment has in CD, as it does not consider other intrinsic factors such as mutations in non-autophagy related genes which have been shown to contribute to CD pathogenesis. Indeed, proteins like PARP-2, IFI35, S100A12, CRP and S100A8 have been shown to contribute to IBD pathogenesis (Cheluvappa et al, 2014;de Jong et al, 2006;Jijon et al, 2000;Leach and Day, 2006;Vermeire et al, 2006). These biomarkers are indicative of an inflammatory state, some of them are mostly detected in the serum, but looking for indicators from faecal samples predict more accurately the state of CD.…”

The Link between the Appendix and Ulcerative Colitis: Clinical Relevance and Potential Immunological Mechanisms

“…Th ey demonstrated that, irrespective of familial predisposition, before the age of 20 years there was a signifi cantly reduced risk of UC in patients who underwent an appendectomy for appendicitis (standardized incidence ratio 0.45, 95% confi dence interval 0.39-0.53), whereas an appendectomy without underlying infl ammation was not associated with a reduced risk (standardized incidence ratio 1.04, 95% confi dence interval 0.95-1.15) ( 17 ). Th e fi nding that an appendectomy may only be eff ective in case of appendicitis was rather new and confi rmed in mouse studies ( 21,22 ).…”

Effect of appendicectomy on colonic inflammation and neoplasia in experimental ulcerative colitis

“…These authors observed that the appendiceal inflammatory process followed an induction sequence of polymorphonuclear cells and then CD4 and CD8 lymphocytes, with an increase of 66 per cent in the proportion of CD25 + FoxP3 + regulatory cells, mostly in mice less than 10 weeks old 5 . In this model of appendicitis followed by appendicectomy in WT mice (without colitis), the distal colonic mucosa exhibits T helper 17 cell (Th17) cytokine-related gene alterations 15 and a pronounced autophagy gene suppression 16 . The IL10/Nox1 DKO mouse model in the present study demonstrates that the degree of appendiceal inflammation is inversely correlated with the severity of colitis.…”