Joint production of IL-22 participates in the initial phase of antigen-induced arthritis through IL-1β production.
BACKGROUND
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by neutrophil articular infiltration, joint pain and the progressive destruction of cartilage and bone. IL-22 is a key effector molecule that plays a critical role in autoimmune diseases. However, the function of IL-22 in the pathogenesis of RA remains controversial. In this study, we investigated the role of IL-22 in the early phase of antigen-induced arthritis (AIA) in mice.


METHODS
AIA was induced in C57BL/6, IL-22(-/-), ASC(-/-) and IL-1R1(-/-) immunized mice challenged intra-articularly with methylated bovine serum albumin (mBSA). Expression of IL-22 in synovial membranes was determined by RT-PCR. Articular hypernociception was evaluated using an electronic von Frey. Neutrophil recruitment and histopathological analyses were assessed in inflamed knee joint. Joint levels of inflammatory mediators and mBSA-specific IgG concentration in the serum were measured by ELISA.


RESULTS
The IL-22 mRNA expression and protein levels in synovial tissue were increased during the onset of AIA. In addition, pharmacological inhibition (anti-IL-22 antibody) and genetic deficiency (IL-22(-/-) mice) reduced articular pain and neutrophil migration in arthritic mice. Consistent with these findings, recombinant IL-22 joint administration promoted articular inflammation per se in WT mice, restoring joint nociception and neutrophil infiltration in IL-22(-/-) mice. Moreover, IL-22-deficient mice showed reduced synovitis (inflammatory cell influx) and lower joint IL-1β levels, whereas the production of IL-17, MCP-1/CCL2, and KC/CXCL1 and the humoral immune response were similar, compared with WT mice. Corroborating these results, the exogenous administration of IL-22 into the joints induced IL-1β production in WT mice and reestablished IL-1β production in IL-22(-/-) mice challenged with mBSA. Additionally, IL-1R1(-/-) mice showed attenuated inflammatory features induced by mBSA or IL-22 challenge. Articular nociception and neutrophil migration induced by IL-22 were also reduced in ASC(-/-) mice.


CONCLUSIONS
These results suggest that IL-22 plays a pro-inflammatory/pathogenic role in the onset of AIA through an ASC-dependent stimulation of IL-1β production.
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. larifarm@gmail.com.
Larissa G
LG
Pinto
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. jhimmytal@yahoo.com.br.
Jhimmy
J
Talbot
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. rsperes87@gmail.com.
Raphael S
RS
Peres
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. rafaelfranca@usp.br.|Present Address: Aggeu Magalhaes Research Center, Oswaldo Cruz Foundation - FIOCRUZ, Avenida Profesor Moreaes Rego s/n, Recife, 50740-465, Brazil. rafaelfranca@usp.br.
Rafael F
RF
Franca
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. shferrei@fmrp.usp.br.
Sérgio H
SH
Ferreira
Université d'Orléans and CNRS, UMR 7355 Molecular and Experimental Immunology and Neurogenetics, 3b rue de la Férollerie, 45071, Orléans, France. bryffel@cnrs-orleans.fr.
Bernhard
B
Ryffel
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. jcafilho@usp.br.
José Carlos F
JC
Aves-Filho
Laboratory of Pathology, School of Medicine, University of Brasilia, Campus Universitário Darcy Ribeiro, Brasilia, 70910-900, Brazil. ffpesca@gmail.com.
Florêncio
F
Figueiredo
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. thicunha@usp.br.
Thiago M
TM
Cunha
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. fdqcunha@fmrp.usp.br.
Fernando Q
FQ
Cunha
D000818:Animals; D000941:Antigens / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018771:Arthralgia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002465:Cell Movement / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007719:Knee Joint / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism; D013585:Synovitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015054:Zymosan / Q000276:immunology; D000097043:Interleukin-22
D000941:Antigens; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D053583:Interleukin-1beta; D007378:Interleukins; D015054:Zymosan; D000097043:Interleukin-22; C498534:Pycard protein, mouse