Abstract:

Objective To investigate whether psychological stress causes duodenal inflammation and the related molecular mechanisms. Methods This study employed a chronic restraint stress （CRS） mouse model， which was supplemented with in vitro models using RAW264.7 and THP-1 monocytic/macrophage cell lines. Techniques including RT-qPCR， Western blot， HE staining， and immunohistochemistry were used to investigate the expression alterations of inflammatory cytokines， pyroptosis pathway-related proteins， and hormone receptors. Results CRS significantly triggered an inflammatory response in the duodenal tissue of mice， which was characterized by heightened levels of inflammatory cytokines such as IL-1β， IL-18， and TNF-α， along with elevated histological scores （P < 0.05）. This pro-inflammatory effect was mediated by the β2-adrenergic receptor （β2AR）， rather than the glucocorticoid receptor. Further research demonstrated that CRS facilitated the proliferation of macrophages in the duodenal mucosa， and the chemical depletion of macrophages effectively inhibited CRS-induced inflammation （P < 0.01）. Mechanistically， CRS activated the classical NLRP3/Caspase1/GSDMD-mediated pyroptosis pathway in duodenal macrophages， as indicated by the increased protein level of the activated N-terminal fragment of GSDMD. In vitro experiments verified that the stress hormone epinephrine could directly activate the macrophage pyroptosis pathway and stimulate the release of inflammatory cytokines via β2AR （P < 0.05）. Conclusions Psychological stress triggers the activation of the sympathetic-adrenal medulla system. This activation promotes GSDMD-mediated pyroptosis in duodenal macrophages through the β2AR signaling pathway， ultimately resulting in duodenal mucosal inflammation.

Key words: β2AR, psychological stress, duodenal inflammation, macrophage, pyroptosis