期刊
ARTHRITIS & RHEUMATOLOGY
卷 70, 期 6, 页码 855-867出版社
WILEY
DOI: 10.1002/art.40447
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资金
- A*STAR National Science Scholarship of Singapore
- NIH (NIAMS) [F31-AR-070094, T32-AI-100853-3]
- NIH [F31-CA-171596-02, R01-AR-056672, R01-AR-068593, R01-HL-125816]
- Instituto de Salud Carlos III
- Fondo Europeo de Desarrollo Regional (Miguel Servet program)
- Arthritis Foundation
- New York University Health and Hospitals Corporation Clinical and Translational Science Institute [UL1-TR-000038-05, UL1-TR-000038-05S1]
- NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS]) [R03-AR-072182, K23-AR-064318]
- Riley Family Foundation
- Beatrice Snyder Foundation
- Judith and Stewart Colton Center for Autoimmunity
- New York University Department of Medicine
- Drs. Martin and Dorothy Spatz Foundation
- ReumaFonds [16-1-403] Funding Source: researchfish
Objective. To introduce a novel preclinical animal model of psoriatic arthritis (PsA) in R26Stat3C(stopfl/fl) CD4Cre mice, and to investigate the role of Th17 cytokines in the disease pathogenesis. Methods. We characterized a novel murine model of Th17-driven cutaneous and synovio-entheseal disease directed by T cell-specific expression of a hyperactive Stat3 allele. By crossing R26Stat3C(stopfl/fl) CD4Cre mice onto an interleukin-22 (IL-22)-knockout background or treating the mice with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines could contribute to the pathogenesis of PsA. Results. R26Stat3C(stopfl/fl) CD4Cre mice developed acanthosis, hyperkeratosis, and parakeratosis of the skin, as well as enthesitis/tendinitis and periarticular bone erosion in different joints, accompanied by osteopenia. T cell-specific expression of a hyperactive Stat3C allele was found to drive the augmented Th17 response in these animals. Careful characterization of the mouse bone marrow revealed an increase in osteoclast progenitor (OCP) and RANKL-producing cells, which contributed to the osteopenia phenotype observed in the mutant animals. Abrogation of the Th17 cytokines IL-17 or IL-22 improved both the skin and bone phenotype in R26Stat3C(stopfl/fl) CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP and RANKL expression on stromal cells. Conclusion. Perturbation of the IL-23/Th17 axis instigates Th17-mediated inflammation in R26Stat3C(stopfl/fl) CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation and bone pathologic features highly reminiscent of human PsA. Both IL-17A and IL-22 produced by Th17 cells appear to play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes PsA.
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