Joint NOD2/RIPK2 Signaling Regulates IL-17 Axis and Contributes to the Development of Experimental Arthritis

Abstract

Intracellular pattern recognition receptors such as the nucleotide-binding oligomerization domain (NOD)-like receptors family members are key for innate immune recognition of microbial infection and may play important roles in the development of inflammatory diseases, including rheumatic diseases. In this study, we evaluated the role of NOD1 and NOD2 on development of experimental arthritis. Ag-induced arthritis was generated in wild-type, NOD1−/−, NOD2−/−, or receptor-interacting serine-threonine kinase 2−/− (RIPK2−/−) immunized mice challenged intra-articularly with methylated BSA. Nociception was determined by electronic Von Frey test. Neutrophil recruitment and histopathological analysis of proteoglycan lost was evaluated in inflamed joints. Joint levels of inflammatory cytokine/chemokine were measured by ELISA. Cytokine (IL-6 and IL-23) and NOD2 expressions were determined in mice synovial tissue by RT-PCR. The NOD2−/− and RIPK2−/−, but not NOD1−/−, mice are protected from Ag-induced arthritis, which was characterized by a reduction in neutrophil recruitment, nociception, and cartilage degradation. NOD2/RIPK2 signaling impairment was associated with a reduction in proinflammatory cytokines and chemokines (TNF, IL-1β, and CXCL1/KC). IL-17 and IL-17 triggering cytokines (IL-6 and IL-23) were also reduced in the joint, but there is no difference in the percentage of CD4+ IL-17+ cells in the lymph node between arthritic wild-type and NOD2−/− mice. Altogether, these findings point to a pivotal role of the NOD2/RIPK2 signaling in the onset of experimental arthritis by triggering an IL-17–dependent joint immune response. Therefore, we could propose that NOD2 signaling is a target for the development of new therapies for the control of rheumatoid arthritis.

NOD1 and NOD2 control the invasiveness of trophoblast cells via the MAPK/p38 signaling pathway in human first-trimester pregnancy

“…NOD2 is a susceptibility gene for both Crohn's disease [35] and rheumatic disease [36], and polymorphisms of NOD1 are associated with inflammatory bowel disease [37] and asthma [38]. Here we have demonstrated for the first time that abnormal expressions of NOD1 and NOD2 are presented in RSA villi, which suggests that pregnancy failure is associated with immunity imbalance.…”

Receptor Interacting Protein-2 acts as negative regulator for nontypeable Haemophilus influenzae-induced mucin MUC5AC expression

“…Previous studies have shown the role of RIP-2 to be complex in various diseases. For example, RIP-2 deficient mice were shown to be resistant to developing arthritis and autoimmunemediated cephalomyelitis associated with a multiple sclerosis model [9,19,20]. Paradoxically, dysregulation of the NOD2/RIP-2 pathway has been implicated in dysregulation of cell signaling pathways during viral infection [9,21].…”

Epicutaneous Immunization with TNP-Ig and Zymosan Induces TCRαβ+ CD4+ Contrasuppressor Cells That Reverse Skin-Induced Suppression via IL-17A

“…It seems that in our model of contrasuppression Dectin-1 is involved. Alternatively, Dectin-1 and Dectin-2 may work in concert with innate receptor, NOD2 [30] other than TLR2 or MyD88 to reverse skin-induced suppression.…”