title: WNT-inflammasome signaling mediates NOD2-induced development of acute arthritis in mice.
abstract: In addition to its role in innate immunity, the intracellular pathogen sensor nucleotide-binding oligomerization domain 2 (NOD2) has been implicated in various inflammatory disorders, including the development of acute arthritis. However, the molecular mechanisms involved in the development of NOD2-responsive acute arthritis are not clear. In this study, we demonstrate that NOD2 signals to a cellular protein, Ly6/PLAUR domain-containing protein 6, in a receptor-interacting protein kinase 2-TGF-β-activated kinase 1-independent manner to activate the WNT signaling cascade. Gain- or loss-of-function of the WNT signaling pathway in an in vivo experimental mouse arthritis model or in vitro systems established the role for WNT-responsive X-linked inhibitor of apoptosis during the development of acute arthritis. Importantly, WNT-stimulated X-linked inhibitor of apoptosis mediates the activation of inflammasomes. The subsequent caspase-1 activation and IL-1β secretion together contribute to the phenotypic character of the inflammatory condition of acute arthritis. Thus, identification of a role for WNT-mediated inflammasome activation during NOD2 stimulation serves as a paradigm to understand NOD2-associated inflammatory disorders and develop novel therapeutics.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India; and.
authors.forename: Vikas
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India; and.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.affiliation: Central Animal Facility, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Subbaraya G
authors.initials: SG
authors.lastname: Ramachandra
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India; and balaji@mcbl.iisc.ernet.in.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D058851:GPI-Linked Proteins; D058847:Inflammasomes / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058851:GPI-Linked Proteins; D058847:Inflammasomes; D020930:MAP Kinase Kinase Kinases; D009419:Nerve Tissue Proteins; D053473:Nod2 Signaling Adaptor Protein; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099151:MAP Kinase Kinase Kinase 7; C545054:Lypd6 protein, mouse; C506255:Ripk2 protein, mouse