PNNL

Abstract

The appendix contains abundant lymphoid tissue and is constantly exposed to gut flora. Appendicitis followed by appendectomy (AA), when done at a young age, prevents or significantly ameliorates Inflammatory Bowel Diseases (IBDs) in later life. IBD comprises Crohn’s disease and ulcerative colitis. Our murine AA model is the only existing experimental model of AA. In our unique model, AA performed in the most proximal colon limits colitis pathology in the most distal colon by curbing T helper 17 cell activity, diminishing autophagy, modulating interferon activity-associated molecules, and suppressing endothelin vasoactivity-mediated immunopathology. In the research presenting in this paper, we have examined the role of chemokines in colitis pathology with our murine AA model. Chemokines are a family of small cytokines with 4 conserved cysteine residues. Chemokines induce chemotaxis in adjacent cells with corresponding receptors. All known 40 chemokine genes and 24 chemokine receptor genes were examined for gene expressions levels in distal colons 3 days post-AA and 28 days post-AA. At 28 days post-AA, the chemokine gene CCL5 was significantly upregulated. Furthermore, Gene Set Enrichment Analysis (GSEA) showed upregulation of 7 CCL5-associated gene-sets 28 days post-AA, in contrast to just 1 gene-set downregulated at the same time-point. The chemokine gene CXCL11 was significantly upregulated 3 days post-AA and 28 days post-AA. GSEA showed upregulation of 6 CXCL11-associated gene-sets but no downregulation of any gene-set. At 28 days post-AA, CCL17 gene expression was significantly downregulated. There was no expression of any chemokine receptor gene 3 days post-AA, but CCR10 was the only chemokine receptor gene that displayed differential gene expression (upregulation) 28 days post-AA. No CCR10-associated gene-set were upregulated in GSEA, in contrast to 1 gene-set downregulated. Our analysis resulted in identifying 3 new therapeutic targets towards ameliorating colitis: CCL5, CXCL11, and CCL17. While CCL5 and CXCL11 are good therapeutic chemokine candidates to be exogenously administered. CCL17 is a good candidate chemokine to competitively inhibit towards limiting colitis pathology.