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Alternative p38 mitogen-activated protein kinases are essential for collagen-induced arthritis

Significance Statement

The role of most p38MAPK isoforms in inflammatory arthritis is not known. In this study we demonstrate the role of p38g and p38d as essential components in arthritis pathogenesis. We used mice lacking p38g and/or p38d to analyse the effect of these isoforms on the development of collagen-induced arthritis (CIA).

Compound p38g and p38d deficiency markedly reduced arthritis severity compared with that in WT mice, whereas lack of either p38g or p38d had an intermediate effect.  Joint damage was minimal in arthritic p38g/d-/- compared with WT mice.  p38g/d-/- mice had lower levels of pathogenic anti-collagen antibodies and of the cytokines interleukin (IL)-1b and tumour necrosis factor (TNF)-a than controls. In vitro T cell assays showed reduced proliferation, interferon (IFN)g and IL-17 production by lymph node cells from p38g/d-/- mice.  mRNA expression of IL-17 and IFNg in joints was significantly inhibited in p38g/d-/- mice. Moreover, p38g/d-/-mice showed a lower Th17 cell frequency and a greater Treg/Th17 ratio than WT mice, both of which are linked to successful therapy in RA. Bone marrow transfer experiments indicated that p38g and p38d expression by non-haematopoietic stromal cells drives collagen-induced arthritis progression, but is not necessary in the haematopoietic compartment. This observation is unexpected, given that p38g/d-/- mice have reduced IL17- and IFNg-producing T cells.  It is nonetheless supported by a report that synovial stromal cells induce increased Th17 cell expansion in the human system, and is also consistent with the view that local synovial inflammatory cells are responsible for the perpetuation of autoimmune inflammation. Our results indicate that p38g and p38d isoforms likely play roles in both hematopoietic and non-hematopoietic compartments.

Our data show that p38g and p38d regulate the immune response in collagen-induced arthritis and suppress clinical disease and bone destruction.  The crucial role of p38g/d in synovial inflammation, bone erosion, as well as TNFa, IL-1b, IFNg and IL-17 production suggests that it could serve as a target of therapy in rheumatoid arthritis as an alternative to traditional p38a inhibitors, which have proven minimally effective in human disease.

Alternative p38 mitogen-activated protein kinases are essential for collagen-induced arthritis

Criado G, Risco A, Alsina-Beauchamp D, Pérez-Lorenzo MJ, Escós A, Cuenda A.

Arthritis Rheum. 2013 Dec 24.

Grupo de Enfermedades Inflamatorias y Autoinmunes, Instituto de Investigación Sanitaria Hospital 12 de Octubre “i+12”, Avda. de Córdoba s/n, 28041-Madrid; and Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, 28049-Madrid, Spain

 Abstract

 Objective. The role of most p38MAPK isoforms in inflammatory arthritis is not known. Here we evaluated p38{Gamma} and p38{Delta} deficiency in thecollagen-induced arthritis (CIA) model. Methods. In wild-type, p38{Gamma}-/- , p38{Delta}-/- and p38{Gamma}/{Delta}-/- mice immunized with chicken type II collagen, we evaluated disease activity by semiquantitative scoring and histological assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anti-collagen antibody levels by enzyme-linked immunosorbent assay. Cytokine and p38MAPK isoform expression in joints were determined by quantitative polymerase chain reaction. Results. Compound p38{Gamma} and p38{Delta} deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38{Gamma} or p38{Delta} had an intermediate effect. Joint damage was minimal in arthritic p38{Gamma}/{Delta}-/- compared with WT mice. p38{Gamma}/{Delta} /- mice had lower levels of pathogenic anti-collagen antibodies and of interleukin (IL)-1{Beta} and tumour necrosis factor-{Alpha} than controls. In vitro T cell assays showed reduced proliferation, interferon (IFN){Gamma} and IL-17 production by lymph node cells from p38{Gamma}/{Delta}-/- mice. mRNA expression of IL-17 and IFN{Gamma} in joints was significantly inhibited in p38{Gamma}/{Delta}-/- mice. WT chimeric mice with p38{Gamma}/{Delta}-/- bone marrow did not show decreased collagen-induced arthritis . Conclusion. Reduced disease severity in p38{Gamma} /{Delta}-/- mice was associated with lower cytokine production and anti-collagen antibody responses than in controls, indicating that p38{Gamma} and p38{Delta} are crucial regulators of inflammatory joint destruction in collagen-induced arthritis . p38{Gamma} and p38{Delta} are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses. © 2013 American College of Rheumatology.

Copyright © 2013 American College of Rheumatology.

 

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