Corticotropin-Releasing Hormone Inhibition of NLRP6 Inflammasome and Stress-Induced Enteritis in Mice

Corticotropin-Releasing Hormone NLRP6 Inflammasome Stress-Induced Enteritis
Corticotropin-Releasing Hormone – NLRP6 Inflammasome – Stress-Induced Enteritis

In the June 2013 issue of Gastroenterology, Sun et al. demonstrate that in mice stress is able to inhibit the NOD‐like receptor family pyrin domain containing 6 (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 affects brain–gut interactions, which in turn may exacerbate intestinal disorders such as the irritable bowel syndrome (IBS). Gastrointestinal responses to stress include alterations in motility, visceral hypersensitivity, and intestinal permeability.

Also, it has been suggested that altered gut microflora may contribute to this phenomenon. IBS patients harbor altered gut microbiota, and probiotics and antibiotics have been shown to be beneficial in patients with IBS, suggesting that the gut microbiota may play an important role in the pathogenesis of IBS.

Viruses and bacteria induce host signalling, which result in a variety of host responses to such infection. These so‐called microbe‐associated molecular patterns (MAMPs) can be sensed by host pattern recognition receptors (PRRs), which initiate innate immune responses. Apart from MAMPs, sterile stressors associated with host cell damage such as ATP or heat‐shock proteins, termed damage‐associated molecular patterns (DAMPs), are likewise sensed by PRRs. PRRs are localized either extracellularly like the Toll‐like receptors (TLR) or intracellularly like the nucleotide oligomerization domain (NOD)‐like receptors (NLRs), enabling the cell to sense both extra‐ and intracellular stressors and infections.

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 fact, the NOD‐like receptor family pyrin domain containing 6 (NLRP6), a member of the NOD‐like receptor (NLR) family, acts as a cytosolic innate immune sensor that recognizes microbe‐associated molecular patterns. In some circumstances upon activation, NLRP6 recruits the adaptor apoptosis‐associated speck‐like protein (ASC) and the inflammatory caspase‐1 or caspase‐11 to form an inflammasome, which mediates the maturation and secretion of the pro‐inflammatory cytokines IL‐18 and IL‐1β.

In other contexts, NLRP6 can exert its function in an inflammasome‐independent manner. Tight regulation of the NLRP6 inflammasome is critical in maintaining tissue homeostasis, while improper inflammasome activation may contribute to the development of multiple diseases. In intestinal epithelial cells, the NLRP6 inflammasome is suggested to play a role in regulating gut microbiome composition, goblet cell function and related susceptibility to gastrointestinal inflammatory, infectious and neoplastic diseases. NLRP6 belongs to the NLR family and together with NLRP1, NLRP3, NLRP7 and NLRC4 constitutes a capacity to build a fully operational inflammasome.

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. The authors studied the involvement of NLRP6 in stress-related intestinal pathology using a murine water-avoidance stress (WAS) model. Mice were subjected to WAS, and intestinal tissue was subsequently noted to be inflamed.

The authors found that 1 hour of WAS daily for 10 days produced significant small intestinal pathology in mice. They also found that WAS-induced CRH production inhibited intestinal NLRP6 expression and led to the development of intestinal pathology. Several previous studies have shown the proinflammatory effect of CRH on mouse intestine.

Thus, 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.

Stress also has been described as a risk factor for IBS in human beings. Although IBS is a diagnosis of exclusion in the absence of pathology, there is a subset of patients, especially those with postinfectious IBS, who have mild inflammation in the colon.

In conclusion, exposure of mice to stress inhibits NLRP6 and alters the composition of the gut microbiota, leading to intestinal inflammation. The study suggests that stress-induced CRH inhibition of NLRP6 inflammasome signaling may play a role in WAS-induced intestinal pathology by inducing fecal dysbiosis. 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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