Abstract
Inflammatory bowel diseases (IBD) is the result of dysregulation of mucosal innate and adaptive immune responses. Factors such as genetic, microbial and environmental are involved in the development of these disorders. Accordingly, animal models that mimic human diseases are tools for the understanding the immunological processes of the IBD as well as to evaluate new therapeutic strategies. Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect. Thus, we aimed to evaluate the modulatory effect of CTX in a murine model of colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS). The CTX was administered intraperitoneally 18 hours after the TNBS intrarectal instillation in BALB/c mice. The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis. Furthermore, the levels of TNF-α, IL-1β and IL-6 were lower in colon tissue homogenates of TNBS-mice that received the CTX when compared with untreated TNBS mice. The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice. In contrast, increased CD4+FoxP3+ cell population as well as secretion of TGF-β, prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) was observed in TNBS-colitis mice treated with CTX compared with untreated TNBS-colitis mice. In conclusion, the CTX is able to modulate the intestinal acute inflammatory response induced by TNBS, resulting in the improvement of clinical status of the mice. This effect of CTX is complex and involves the suppression of the pro-inflammatory environment elicited by intrarectal instillation of TNBS due to the induction of a local anti-inflammatory profile in mice.
Highlights
Immune tolerance is responsible for controlling inflammation in the gastrointestinal tract, limiting the response against antigens derived from food and commensal bacteria [1, 2, 3]
Considering that the CTX from C.d.terrificus venom exerts a potent immunomodulatory effect, we investigated in this work the ability of this toxin to interfere with the development of the murine model of acute colitis induced by trinitrobenzene sulfonic acid (TNBS)
To address the modulatory effect of CTX on the intestinal inflammatory process, groups of mice received the intrarectal instillation of TNBS and after 18 h, the toxin was injected i.p
Summary
Immune tolerance is responsible for controlling inflammation in the gastrointestinal tract, limiting the response against antigens derived from food and commensal bacteria [1, 2, 3]. A breakdown in this tolerogenic status due to distinct factors such as genetic or environmental can result in a dysregulated immunological response and consequent inflammatory bowel disease (IBD) [4, 5, 6, 7, 8]. The IL-22 is their cytokine marker mediating distinct functions such as epithelial cells activation in the intestinal tissue [13]. Secretion of IL-17A as well as IL-22 by this cell population has been implicated in the intestinal immunity to enteric pathogens [14, 15]. ILC3 secreting IL-17A are involved in the inflammation observed in distinct models of IBD [16, 17]
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