Corticotropin-Releasing Hormone’s Inhibition of NLRP6 Inflammasome May Trigger Stress-Induced Enteritis in Mice

Corticotropin-Releasing Hormone’s Inhibition Inflammasome

In the June 2013 issue of Gastroenterology, Sun et al. demonstrate that in mice stress is able to inhibit NLRP6, through a corticotropin-releasing hormone (CRH)-dependent mechanism and to modify the composition of the gut microbiota, leading to intestinal inflammation.

It is well known that psychological stress exacerbates the symptoms of irritable bowel syndrome (IBS). Also, it has been suggested that altered gut microflora may contribute to this phenomenon, given improvement noted in these patients following probiotic and antibiotic treatment.

The NOD-like Receptors (NLRs) are intracellular microbial sensors that are critical for the initiation of the innate immune response. Some of them also sense non-microbial danger signals and form large cytoplasmic complexes called inflammasomes.

These complexes typically link the sensing of microbial products to the proteolytic activation of the proinflammatory cytokines (Martinon F., Mayor A. & Tschopp J., Annu Rev Immunol. 2009; 27:229).

In the Gastroenterology study, the authors focus on the nucleotide-binding oligomerization domain protein-like receptors, pyrin-domain containing (NLRP6) inflammasome.

It regulates intestinal microflora, as previous studies have shown that a deficiency in NLRP6 can promote increased susceptibility to intestinal inflammation. Mice were subjected to water-avoidance stress (WAS), and intestinal tissue was subsequently noted to be inflamed.

NLRP6 expression was also markedly decreased in the intestines of stressed animals, and this seemed to be associated with rises in corticotropin-releasing hormone (CRH) following stress.

Of note, peripherally expressed CRH can often act as a potent proinflammatory factor (K. Karalis et al., Science, 1991, 254:421), in contrast to the hypothalamic CRH – a central mediator of the stress response that ultimately results in increased release of glucocorticoids.

With this study, Sun et al. propose a pathway for stress-mediated intestinal changes and identify potential therapeutic targets for the management of intestinal disorders exacerbated by stress.

Source: Gastroenterology, 2013, 144:1478-87, 1487.e1-8. doi: 10.1053/j.gastro.2013.02.038. Epub 2013 Mar 5.
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