Activation of neuronal P2X7 receptor–pannexin-1 mediates death of enteric neurons during colitis

Abstract

Inflammatory bowel diseases (IBD) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons1,2. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here we report using in vivo models of experimental colitis that inflammation causes enteric neuron death by activating a neuronal signaling complex comprised of P2X7 receptors (P2X7Rs), pannexin–1 (Panx1) channels, Asc and caspases. Inhibiting P2X7Rs, Panx1, Asc or caspase activity prevents inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression is reduced in Crohn’s disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and subsequent development of the abnormal gut motility in IBD. Targeting Panx1 represents a novel neuroprotective strategy to ameliorate the progression of IBD–associated dysmotility.

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…Further, P2X7 receptor stimulation of enteric neurons elicits a direct release of ATP onto glia through Panx1 (Gulbransen et al, 2012). By way of this paracrine signaling, the P2X7 receptor can function as a gatekeeper between glia and neurons to regulate inflammatory cascades (Browne, 2013).…”

<em>In Situ</em> Ca²⁺ Imaging of the Enteric Nervous System

“…Imaging Ca 2+ transients in neurons and glia with fluorescent dyes is an established and widely used technique to study the functional organization and dynamics of the ENS [13][14][15][16][17] . Ca 2+ imaging has been shown to be an important tool in studying intact GI tissue segments to elucidate the spread of excitability through ICC pacemaker networks 18 and gut smooth muscle 19,20 .…”

PYCARD (PYD and CARD domain containing)

“…Note ASC triggers caspase-driven enteric neuronal cell death in response to inflammatory driven ATP activation of P2X7R and pannexin channels (Gulbransen et al, 2012). Alterations in the NLRP6 inflammasome pathway including ASC, caspase-1 and IL-18 may contribute to the etiology of human inflammatory bowel disease (Elinav et al, 2011).…”