Endoplasmic reticulum stress regulates intestinal motility in acute pancreatitis by regulating the expression and phosphorylation of nNOS through IRE1α/XBP1s-PI3K/Akt signaling axis

Intestinal dysmotility is a major complication that significantly impacts the prognosis of acute pancreatitis (AP). The neuronal nitric oxide synthase (nNOS) -expressing neurons within the enteric nervous system promote intestinal relaxation via the release of nitric oxide (NO). As the rate-limiting enzyme of NO synthesis, nNOS directly regulates NO production, thereby modulating intestinal motility. However, the upstream regulatory mechanisms involved in nNOS in intestinal dysmotility during AP remain unclear. In this study, we delved into the molecular mechanisms of intestinal motility regulation in AP through rats, enteric neuronal cells (ENCs), and intestinal smooth muscle cells (ISMCs). We found that the activation of PI3K/Akt pathway increased the protein expression of nNOS and its phosphorylation at Ser1417, and NO production in AP rats and LPS-stimulated ENCs. This led to reduced contractile activity and migratory capacity of ISMCs during co-culture and impaired intestinal smooth muscle strip contractile activity. Inhibition of PI3K/Akt pathway by LY294002 improved these effects. Further experiments demonstrated that during AP, endoplasmic reticulum stress (ERS) occurred within ENCs, manifested by endoplasmic reticulum expansion and activation of the IRE1α/XBP1s pathway. This promoted XBP1s binding to PI3K and Akt, activating this pathway and downstream effects. Inhibition of IRE1α/XBP1s pathway by toyocamycin further inhibited PI3K/Akt pathway and downstream effects. In conclusion, ERS in ENCs activates the IRE1α/XBP1s-PI3K/Akt signaling axis during AP, which upregulates the expression of nNOS and its phosphorylation at Ser1417, which increases NO production, and thus reduces the contractile activity and migratory capacity of ISMCs, ultimately causing intestinal dysmotility.

Acute pancreatitis; Endoplasmic reticulum stress; IRE1α/XBP1s pathway; Intestinal dysmotility; PI3K/Akt pathway; nNOS.