Abstract
Transient Receptor Potential Ankyrin 1 (TRPA1) channels are localized on sensory nerves and several non-neural cells, but data on their functional significance are contradictory. We analysed the presence and alterations of TRPA1 in comparison with TRP Vanilloid 1 (TRPV1) at mRNA and protein levels in human and mouse intact and inflamed colons. The role of TRPA1 in a colitis model was investigated using gene-deficient mice. TRPA1 and TRPV1 expressions were investigated in human colon biopsies of healthy subjects and patients with inflammatory bowel diseases (IBD: ulcerative colitis, Crohn's disease) with quantitative PCR and immunohistochemistry. Mouse colitis was induced by oral 2% dextran-sulphate (DSS) for 10 days. For investigating the functions of TRPA1, Disease Activity Index (weight loss, stool consistency, blood content) was determined in C57BL/6-based Trpa1-deficient (knockout: KO) and wildtype (WT) mice. Sensory neuropeptides, their receptors, and inflammatory cytokines/chemokines were determined with qPCR or Luminex. In human and mouse colons TRPA1 and TRPV1 are located on epithelial cells, macrophages, enteric ganglia. Significant upregulation of TRPA1 mRNA was detected in inflamed samples. In Trpa1 KO mice, Disease Activity Index was significantly higher compared to WTs. It could be explained by the greater levels of substance P, neurokinins A and B, neurokinin 1 receptor, pituitary adenylate-cyclase activating polypeptide, vasoactive intestinal polypeptide, and also interleukin-1beta, macrophage chemoattractant protein-1, monokine induced by gamma interferon-1, tumor necrosis factor-alpha and B-lymphocyte chemoattractant in the distal colon. TRPA1 is upregulated in colitis and its activation exerts protective roles by decreasing the expressions of several proinflammatory neuropeptides, cytokines and chemokines.
Highlights
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are the most common chronic inflammatory disorders of the intestine
Tumor colon biopsies, used for comparison in the present study, express TRP Vanilloid 1 (TRPV1) and Transient Receptor Potential Ankyrin 1 (TRPA1) local mRNA gene expression but do not exhibit significant change in their gene expression levels compared to non-inflamed controls
We have found TRPA1 and TRPV1 gene expression and immunostaining in the mouse and human colon
Summary
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are the most common chronic inflammatory disorders of the intestine. UC affects only the colon, CD may affect all parts of the gastrointestinal tract, but most commonly the distal part of the small intestine, the ileum, and the colon. Through chemically damaging the epithelial barrier, DSS induces colonic inflammation and ulceration leading to progressive crypt loss in the colonic mucosa, alterations of luminal bacterium species and activation of inflammatory cells [2,3]. Available immunosuppressive therapies are associated with potential significant adverse effects and there remains a cohort of patients with refractory or relapsing disease. This poses a driving force to understand the complex pathophysiological mechanisms, identify key mediators and find novel therapeutic targets [4]
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