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.