Inhibition of Ras GTPases prevents Collagen‐Induced Arthritis by Reducing the Generation of Pathogenic CD4+ T Cells and the Hyposialylation of Autoantibodies

Autor: Morad Zayoud, Einav Vax, Galit Elad‐Sfadia, Iris Barshack, Ronit Pinkas‐Kramarski, Itamar Goldstein
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: ACR Open Rheumatology, Vol 2, Iss 9, Pp 512-524 (2020)
Druh dokumentu: article
ISSN: 2578-5745
DOI: 10.1002/acr2.11169
Popis: Objective RasGTPases are master regulators of multiple intracellular signaling cascades. Perturbation of this pathway has been implicated in the pathogenesis of rheumatoid arthritis (RA). In this study we aimed to define the therapeutic potential of a novel RasGTPases inhibitor, farnesylthiosalicylate (FTS), in the preclinical mouse model of collagen‐induced arthritis (CIA) and better delineate its immunomodulatory effects both ex vivo and in the mouse. Methods We analyzed in vitro the immunomodulatory effects of FTS on various CD4+ T‐cell functions such as activation, proliferation, T‐helper polarization, and production of proinflammatory cytokines. Using the CIA model, we further determined the efficacy of FTS to inhibit clinical, histopathologic, and diverse immunological outcomes of arthritis. Results FTS treatment of CD4+ T cells in vitro effectively targeted distinct kinases (extracellular signal‐regulated kinase 1/2, p38, protein kinase B/AKT, and mammalian target of rapamycin), the production of interleukin (IL)‐17A, IL‐22, and granulocyte‐macrophage colony‐stimulating factor, and Th17 polarization. FTS therapy in the mouse CIA model significantly reduced clinical disease severity and joint inflammation/damage by histology. Importantly, FTS suppressed the in vivo induction of splenic IL‐17+IL‐22+ Th17 cells and the secretion of proinflammatory cytokines. The production of pathogenic autoantibodies and their abnormal hyposialylation was significantly attenuated by FTS therapy. Importantly, in vivo generation of collagen type‐II specific effector CD4+ T cells was likewise repressed by FTS therapy. Conclusion The RasGTPases inhibitor FTS attenuates the production of proinflammatory cytokines by in vitro–activated T cells and is a potent immunomodulatory compound in the CIA model, primarily targeting the generation of autoreactive Th17 cells and the production of autoantibodies and their subsequent pathogenic hyposialylation.
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