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.

Nucleotide-binding oligomerization domain-containing protein 2 prompts potent inflammatory stimuli during Neospora caninum infection

“…In a distinct manner than that observed for Nod2, genetic depletion of Rip2 did not increase mice survival against lethal challenge, nor did alter IL-6 production and lesions observed in the pancreas. This finding, though unexpected, is consistent with some published results demonstrating that Nod2 can interact with others known innate pathways, such as those coordinated by mitochondrial antiviral signaling (MAVS), caspase activation and recruitment domain 9 (CARD9) and Ly6/PLAUR domain–containing protein 6 (LYPD6) 24 35 36 .…”

Ac2PIM-responsive miR-150 and miR-143 Target Receptor-interacting Protein Kinase 2 and Transforming Growth Factor Beta-activated Kinase 1 to Suppress NOD2-induced Immunomodulators

“…Of note, though classical NOD2 responses via RIP2 and TAK1 are well established, various previous investigations have suggested that MDP-induced NOD2 responses could be RIP2/ TAK1-independent (42,43). However, in the current study, we found role for the classical NOD2 responses.…”

“…While MDP-triggered NOD2 signals to activate PI3K-PKC-MAPK pathways in macrophages and dendritic cells (8,18,20), PI3K-PKC-MAPK pathway was also previously found to regulate the immunomodulators like COX-2, SOCS-3, and MMP-9 in macrophages on TLR2 stimulation by mycobacteria (62)(63)(64). Of note, NOD2-responsive ␤-catenin signaling exacerbates several pathologies including inflammatory disorders and arthritis (42,65). ␤-Catenin also regulates COX-2 and SOCS-3 expression during mycobacterial infection (66).…”

Activation of the Wnt Pathway by Mycobacterium tuberculosis: A Wnt–Wnt Situation

“…The intracellular pathogen sensor NOD2, which is activated by bacterial cell wall components like peptidoglycan, specifically by muramyl dipeptide (MDP), has been shown to be activated during macrophage infection with M. tuberculosis and to synergize with the TLR signaling pathway to promote the production of pro-inflammatory cytokines ( 59 – 61 ). Interestingly, last year, it was suggested that the activation of NOD2 by MDP results in the activation of the Wnt pathway ( 62 ). In the presence of MDP, NOD2 is translocated to the membrane where it interacts with the Ly6/PLAUR domain-containing protein 6, which has been previously shown to be recruited to the Wnt receptor complex and promotes Wnt signaling ( 63 ) that results in β-catenin nuclear translocation and the expression of the X chromosome-linked inhibitor of apoptosis, that in turn activates the NLRP3 inflammasome leading to IL-1β maturation and secretion ( 62 ).…”