title: Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway.
abstract: Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-d-aspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a β-arrestin-2 NF-kβ and JNK pathway and not via Ca(2+) mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut; Section of Internal Medicine, Catholic Health System, University at Buffalo, Buffalo, New York.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Farooq
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut;
authors.forename: Rafaz
authors.initials: R
authors.lastname: Hoque
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut;
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut;
authors.forename: Ahsan
authors.initials: A
authors.lastname: Farooq
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut;
authors.forename: Ayaz
authors.initials: A
authors.lastname: Ghani
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut;
authors.forename: Kaimul
authors.initials: K
authors.lastname: Ahsan
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut;
authors.forename: Mateus
authors.initials: M
authors.lastname: Guerra
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, Connecticut; Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut; and wajahat.mehal@yale.edu.
authors.forename: Wajahat Zafar
authors.initials: WZ
authors.lastname: Mehal
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001224:Aspartic Acid / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010195:Pancreatitis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D000893:Anti-Inflammatory Agents; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011498:Protein Precursors; D016194:Receptors, N-Methyl-D-Aspartate; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D001224:Aspartic Acid; D020170:Caspase 1
keywords: aspartate
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