PDF(Pubmed)
Abstract：
Psychological stress increases risk of gastrointestinal tract diseases. However, the mechanism behind stress-induced gastrointestinal injury is not well understood. The objective of our study is to elucidate the putative mechanism of stress-induced gastrointestinal injury and develop an intervention strategy. To achieve this, we employed the restraint stress mouse model, a well-established method to study the pathophysiological changes associated with psychological stress in mice. By orally administering gut-nonabsorbable Evans blue dye and monitoring its plasma levels, we were able to track the progression of gastrointestinal injury in live mice. Additionally, flow cytometry was utilized to assess the viability, death, and inflammatory status of splenic leukocytes, providing insights into the stress-induced impact on the innate immune system associated with stress-induced gastrointestinal injury. Our findings reveal that neutrophils represent the primary innate immune leukocyte lineage responsible for stress-induced inflammation. Splenic neutrophils exhibited elevated expression levels of the pro-inflammatory cytokine IL-1, cellular reactive oxygen species, mitochondrial burden, and cell death following stress challenge compared to other innate immune cells such as macrophages, monocytes, and dendritic cells. Regulated cell death analysis indicated that NETosis is the predominant stress-induced cell death response among other analyzed regulated cell death pathways. NETosis culminates in the formation and release of neutrophil extracellular traps, which play a crucial role in modulating inflammation by binding to pathogens. Treatment with the NETosis inhibitor GSK484 rescued stress-induced neutrophil extracellular trap release and gastrointestinal injury, highlighting the involvement of neutrophil extracellular traps in stress-induced gastrointestinal inflammation. Our results suggest that neutrophil NETosis could serve as a promising drug target for managing psychological stress-induced gastrointestinal injuries.
摘要：
心理压力增加胃肠道疾病的风险。然而,应激引起的胃肠道损伤背后的机制尚不清楚。我们研究的目的是阐明应激性胃肠道损伤的推定机制并制定干预策略。为了实现这一点，我们采用束缚应激小鼠模型，研究与小鼠心理应激相关的病理生理变化的方法。通过口服肠道不可吸收的伊文思蓝染料并监测其血浆水平，我们能够追踪活体小鼠胃肠道损伤的进展。此外,流式细胞术用于评估活力，死亡,和脾白细胞的炎症状态，提供对应激诱导的对与应激诱导的胃肠道损伤相关的先天免疫系统的影响的见解。我们的发现表明，中性粒细胞代表负责应激诱导的炎症的主要先天免疫白细胞谱系。脾中性粒细胞显示促炎细胞因子IL-1，细胞活性氧的表达水平升高，线粒体负荷，与其他先天免疫细胞如巨噬细胞相比，应激挑战后的细胞死亡，单核细胞,和树突状细胞。调节的细胞死亡分析表明，NETosis是其他分析的调节的细胞死亡途径中主要的应激诱导的细胞死亡反应。NETosis最终形成和释放中性粒细胞胞外陷阱，通过与病原体结合在调节炎症中起关键作用。用NETosis抑制剂GSK484治疗可挽救应激诱导的中性粒细胞胞外阱释放和胃肠道损伤，强调中性粒细胞胞外陷阱参与应激诱导的胃肠道炎症。我们的结果表明，中性粒细胞NETosis可以作为管理心理压力引起的胃肠道损伤的有希望的药物靶标。
