A novel P2X2-dependent purinergic mechanism of enteric gliosis in intestinal inflammation.
A novel P2X2-dependent purinergic mechanism of enteric gliosis in intestinal inflammation.
复制标题
肠道炎症中肠胶质瘤的p2x2依赖性嘌呤能新机制。
DOI：
10.15252/emmm.202012724
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发表时间：
2021-01-11
影响因子：
11.1
通讯作者：
Wehner S
中科院分区：
文献类型：
--
作者：
Schneider R;Leven P;Glowka T;Kuzmanov I;Lysson M;Schneiker B;Miesen A;Baqi Y;Spanier C;Grants I;Mazzotta E;Villalobos-Hernandez E;Kalff JC;Müller CE;Christofi FL;Wehner S
肠胶质细胞（EGC）调节运动，维持肠道稳态，并导致肠道疾病和运动障碍中的神经炎症。损伤会诱导一种被称为“神经胶质增生”的反应性神经胶质表型，但人们对“肠神经胶质增生”的诱导机制和触发因素的分子特性知之甚少。我们测试了这样的假设：肠道手术期间的手术创伤会触发 ATP 释放，从而驱动肠神经胶质增生和炎症，从而导致术后肠梗阻 (POI) 运动受损。 p38 依赖性 MAPK 通路的 ATP 激活会触发小鼠（和人类）EGC 中的细胞因子释放和神经胶质增生表型。受体拮抗和基因缺失研究表明 P2X2 是相关的 ATP 受体，药理学筛选确定氨溴索是一种新型 P2X2 拮抗剂。氨溴索可预防 ATP 诱导的肠神经胶质增生、炎症，并防止运动障碍，同时消除受到手术创伤的人体肠道中的肠神经胶质增生。我们在人类和小鼠中发现了 ATP 诱导的肠神经胶质增生、炎症和运动障碍的一种新的致病性 P2X2 依赖性途径。创伤期间阻断肠道神经胶质 P2X2 受体的干预措施可能是治疗 POI 和免疫驱动的肠道动力障碍的一种新疗法。肠神经胶质增生被证明是腹部手术时肠道免疫反应的一部分。 ATP 通过选择性嘌呤能受体信号传导激活小鼠和人类的肠神经胶质细胞。新发现的 P2X2 拮抗剂氨溴索可抑制这一致病途径，从而阻断 ATP 诱导的肠神经胶质增生，并预防术后肠梗阻。
Enteric glial cells (EGC) modulate motility, maintain gut homeostasis, and contribute to neuroinflammation in intestinal diseases and motility disorders. Damage induces a reactive glial phenotype known as “gliosis”, but the molecular identity of the inducing mechanism and triggers of “enteric gliosis” are poorly understood. We tested the hypothesis that surgical trauma during intestinal surgery triggers ATP release that drives enteric gliosis and inflammation leading to impaired motility in postoperative ileus (POI). ATP activation of a p38‐dependent MAPK pathway triggers cytokine release and a gliosis phenotype in murine (and human) EGCs. Receptor antagonism and genetic depletion studies revealed P2X2 as the relevant ATP receptor and pharmacological screenings identified ambroxol as a novel P2X2 antagonist. Ambroxol prevented ATP‐induced enteric gliosis, inflammation, and protected against dysmotility, while abrogating enteric gliosis in human intestine exposed to surgical trauma. We identified a novel pathogenic P2X2‐dependent pathway of ATP‐induced enteric gliosis, inflammation and dysmotility in humans and mice. Interventions that block enteric glial P2X2 receptors during trauma may represent a novel therapy in treating POI and immune‐driven intestinal motility disorders. Enteric gliosis was shown to be part of an intestinal immune response upon abdominal surgery. ATP activates enteric glial cells via selective purinergic receptor signalling in mice and humans. Inhibition of this pathogenic pathway by the newly identified P2X2 antagonist ambroxol blocks ATP‐induced enteric gliosis and protects against postoperative ileus.
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影响因子：
4.8
作者：
Bhave, Sukhada;Gade, Aravind;Akbarali, Hamid I.
通讯作者：
Akbarali, Hamid I.
影响因子：
24.5
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Aubé, AC;Cabarrocas, J;Neunlist, M
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Neunlist, M
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Sofroniew MV
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Nilsson, Michael
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作者：
Csoka, Balazs;Nemeth, Zoltan H.;Hasko, Gyoergy
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