| Inflammatory bowel disease(IBD),such as Crohn’s disease and ulcerative colitis, is a chronic, relapsing, and remitting disease characterized by chronic irritation and inflammation in the gastrointestinal tract, and diarrhea, abdominal pain and bloody stool as clinical manifestations. Over 1 million residents in the USA and 2.5 million in Europe are estimated to have IBD. Moreover, IBD has emerged in newly industrialized countries in Asia, South America and has evolved into a global disease with rising prevalence in every continent. IBD is mediated by very complex mechanisms controlled by genetic, environmental, and immune factors. The causes leading to chronic intestinal inflammation in IBD remain elusive. A defective mucosal immune mechanism has been indicated in the pathogenesis of chronic intestinal inflammation. Emerging evidence suggests that psychological stress may affect clinical symptoms of idiopathic IBD.Stress response is natural response or reaction to environmental demands or pressures, including psychological and physical reaction. In response to repeated exposure to various stressors, such as cold and heat, trauma, infection, surgery, anxiety and depression, autonomic nervous system and hypothalamic-pituitary-adrenal(HPA) axis, which is the central stress response system, are activated, resulting in sustained release of catecholamine [such as epinephrine and norepinephrine(NE)] and cortisol in sympathetic neurons, adrenal medulla, and adrenal cortex. Over-release of a variety of neurotransmitters(such as catecholamines and vasoactive intestinal peptide) influences the activities of lymphocytes, macrophages, and neutrophils. Immune cells express adrenergic receptors(ARs), through which locally released NE or circulating catecholamines regulate the production of cytokines and antibodies and the functional activities of immune cells.The present study set out to explore the mechanistic basis of psychological stress-induced colonic tissue injuries in DSS-induced colitis model. We hypothesized that the activation of the stress-associated signaling lowers the threshold for triggering an inflammatory response in acute colitis, resulting in exacerbated colon mucosal damage. Therefore, we investigated the effects of chronic stress on the expression of proinflammatory cytokines and on inflammatory cell recruitment/infiltration in colonic tissues. We further explored the stress-triggered signaling pathways that are involved in the pathogenesis of IBD. Major findings are as follows:1. Psychological stress induces neutrophilia and amplifies the inflammatory response in DSS-induced colitis. We employed a well characterized chemical model to initiate experimental IBD in mice by feeding with 2.5% dextran sulfate sodium(DSS)-containing drinking water. In order to investigate the roles of psychological stress in the colonic inflammation, the mice were subjected to chronic restraint stress(CRS) and chronic unpredictable stress(CUS). Our data show that psychological stress aggravated DSS-induced colitis with more severe diarrhea and colitis characterized by more severe weight loss, colon shortening, more extensive ulceration of the epithelial layer, edema, crypt damage of bowel wall, and massive neutrophil infiltration, and increased epithelial permeability. The stimulation of psychological stress resulted in abnormal expression of the proinflammatory cytokines(IL-1β, IL-6, IL-17 A, and IL-22) and chemokines(CXCL1, CXCL2) and overactivation of the STAT3 signaling pathway. We analyzed the proportion of neutrophils by flow cytometry and immunohistochemistry. The data indicate that psychological stress causes peripheral neutrophilia and amplifies the inflammatory response in IBD mouse model.2. Catecholamines play a key role in chronic stress-induced neutrophil infiltration. The dysregulation of immune response was worsened by the activation of catecholamines-mediated signaling pathways, as β-AR agonist ISO exerted similar effects on colonic damage, neutrophilia, and neutrophil infiltration in DSS-induced colitis and resulted in abnormal expression of the proinflammatory cytokines and chemokines. The β1-AR/β2-AR inhibitor propranolol effectively suppressed the expression of the proinflammatory cytokines and chemokines and phosphorylation of STAT3 imposed by CUS. It seemed to be a weak stimulus for the expression of the chemokines and phosphorylation of STAT3 when NE was added simultaneously to the cells. NE also exerted a chemotactic effect on neutrophil migration. We noticed that the expression of TH, the rate-limiting enzyme in catecholamine biosynthesis was dramatically enhanced in nerve fibers in the muscular wall of the colon and the myenteric ganglia, reflecting elevated activities of adrenergic nervous system. The data demonstrate a pathogenic interplay between the HPA axis, adrenergic nervous system, and the immune system in the pathogenesis of intestinal inflammation.3. Catecholamines enhanced IL-17A-induced neutrophil infiltration through activating the STAT3 signaling pathway. Our data demonstrate that IL-17 A and IL-22 were remarkably upregulated under chronic stress, concomitant with the upregulation of the neutrophil chemokines. Both NE and IL-17 A could induce the phosphorylation of STAT3 in HT29 cells, but combination of NE and IL-17 A produced stronger effect. Co-treatment of CT26 and HT29 cells with IL-17 and ISO produced an enhanced effect on induction of CXCL1 and CXCL2. NE also amplified the effects of IL-17 A on the expression of chemokines and neutrophil migration, indicating the cooperativity of the stress-related hormone and IL-17 in driving neutrophil recruitment and trafficking in IBD. Surprisingly, propranolol did not antagonize the effect of CUS on the expression of IL-17 A and IL-22. It is possible that the changes of the IL-17 and IL-22 expression observed in the present study may be attributed to the activation of other stress-associated pathways.4. Psychological stress enhances DSS-induced inflammatory response through activating β1-AR/β2-AR. In our study, treatment with β3-AR selective blocker SR59230 A failed to alleviate stress-induced damage and neutrophil response in DSS-induced mice, but the β1-AR/β2-AR inhibitor propranolol effectively reduced the numbers of the CD11b+Ly6C+Ly6G+ cells in the circulation, suppressed neutrophil infiltration into colonic tissues, and attenuated the colonic tissue damage imposed by chronic stress, revealing a close linkage between the β1-AR/β2-AR activation and neutrophil trafficking in experimental colitis. In addition, propranolol also remarkably abolished CUS-induced upregulation of proinflammatory cytokines and neutrophil chemokines. The data indicate that chronic stress triggers enhanced inflammatory response through catecholamines-mediated activation of the β1-AR/β2-AR signaling pathways in DSS-induced colitis.In conclusion, the current study discloses that chronic psychological stress upregulates the levels of proinflammatory cytokines and neutrophil chemokines, stimulates neutrophil mobilization, and promotes colonic neutrophil infiltration through catecholamines-mediated β-adrenergic signaling. The sustained presence of the driving stimulus may enhance the vulnerability to experimental colitis, resulting in colonic hypersensitivity, dysfunction, and leukocyte-mediated tissue injury. Our data provide a new insight into the mechanisms underlying the association of psychological stress with excessive inflammatory response and pathophysiological consequences in IBD. The findings also suggest a potential application of neuroprotective agents to prevent relapsing immune activation in the treatment of IBD. |
PDF Full Text Request