title: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo 14049-900, Brazil.
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Rafael F O
authors.initials: RF
authors.lastname: França
authors.forename: Larissa G
authors.initials: LG
authors.lastname: Pinto
authors.forename: Jhimmy
authors.initials: J
authors.lastname: Talbot
authors.forename: Walter M
authors.initials: WM
authors.lastname: Turato
authors.forename: Henrique P
authors.initials: HP
authors.lastname: Lemos
authors.forename: Jonilson B
authors.initials: JB
authors.lastname: Lima
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Sérgio C L
authors.initials: SC
authors.lastname: Almeida
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Paulo
authors.initials: P
authors.lastname: Louzada-Junior
authors.forename: Dario S
authors.initials: DS
authors.lastname: Zamboni
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002478:Cells, Cultured; D020381:Interleukin-17 / Q000378:metabolism* / Q000502:physiology; D007719:Knee Joint / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000172:deficiency; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency / Q000502:physiology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000276:immunology / Q000633:toxicity; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C029180:methylated bovine serum albumin; D012710:Serum Albumin, Bovine; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse