Abstract
Inflammatory bowel diseases (IBDs) 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 neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented 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 was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / pharmacology
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Analysis of Variance
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Animals
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Calcium / metabolism
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Carrier Proteins / genetics
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Caspases / metabolism
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Cell Death / drug effects
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Cell Death / physiology
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Colitis / pathology*
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Connexins / metabolism*
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / metabolism
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Dinitrofluorobenzene / analogs & derivatives
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Dinitrofluorobenzene / pharmacology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Estrenes / pharmacology
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Gastrointestinal Motility / drug effects
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Gastrointestinal Motility / genetics
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myenteric Plexus / pathology*
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nerve Tissue Proteins / metabolism*
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Neurons / drug effects
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Neurons / metabolism*
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Nitric Oxide Synthase Type I / metabolism
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Phosphodiesterase Inhibitors / pharmacology
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Purinergic P2X Receptor Agonists / pharmacology
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Pyrrolidinones / pharmacology
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Receptors, Purinergic P2X7 / metabolism*
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Signal Transduction / drug effects
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Time Factors
Substances
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Connexins
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Cytoskeletal Proteins
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Estrenes
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Glial Fibrillary Acidic Protein
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nerve Tissue Proteins
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Nlrp3 protein, mouse
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Panx1 protein, mouse
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Phosphodiesterase Inhibitors
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Purinergic P2X Receptor Agonists
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Pycard protein, mouse
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Pyrrolidinones
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Receptors, Purinergic P2X7
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1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
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2,4-dinitrofluorobenzene sulfonic acid
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3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
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2',3'-dialdehyde ATP
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Adenosine Triphosphate
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Dinitrofluorobenzene
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Nitric Oxide Synthase Type I
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Caspases
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Calcium