Ras Signaling Inhibitors Attenuate Disease in Adjuvant-Induced Arthritis via Targeting Pathogenic Antigen-Specific Th17-Type Cells

• Published in: Frontiers in immunology Vol. 8; p. 799
• Main Authors: Zayoud, Morad, Marcu-Malina, Victoria, Vax, Einav, Jacob-Hirsch, Jasmine, Elad-Sfadia, Galit, Barshack, Iris, Kloog, Yoel, Goldstein, Itamar
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.07.2017
• Subjects: adjuvant induced arthritis; farnesylthiosalicylic acid; Immunology; Ras GTPases; rheumatoid arthritis; T-helper cells; Ras GTPases; T-helper cells; rheumatoid arthritis; adjuvant induced arthritis; farnesylthiosalicylic acid
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2017.00799

The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T-cell receptor activation by autoantigens. Somatic mutation in or may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization. In the present study, we tested the therapeutic and immunomodulatory effects of FTS and its derivative 5-fluoro-FTS (F-FTS) in the rat adjuvant-induced arthritis model (AIA). We show that AIA severity was significantly reduced by oral FTS and F-FTS treatment compared to vehicle control treatment. FTS was as effective as the mainstay anti-rheumatic drug methotrexate, and combining the two drugs significantly increased efficacy compared to each drug alone. We also discovered that FTS therapy inhibited both the CFA-driven induction of Th17 and IL-17/IFN-γ producing "double positive" as well as the upregulation of serum levels of the Th17-associated cytokines IL-17A and IL-22. By gene microarray analysis of effector CD4 T cells from CFA-immunized rats, re-stimulated with the mycobacterium tuberculosis heat-shock protein 65 (Bhsp65), we determined that FTS abrogated the Bhsp65-induced transcription of a large list of genes (e.g., Il17a/f, Il22, Ifng, Csf2, Lta, and Il1a). The functional enrichment bioinformatics analysis showed significant overlap with predefined gene sets related to inflammation, immune system processes and autoimmunity. In conclusion, FTS and F-FTS display broad immunomodulatory effects in AIA with inhibition of the Th17-type response to a dominant arthritogenic antigen. Hence, targeting Ras signal-transduction cascade is a potential novel therapeutic approach for RA.