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

Abstract

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 NRAS or KRAS 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 in vivo 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 in vitro 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.

The T helper type 17/regulatory T cell imbalance was associated with Ras‐GTPase overexpression in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease

“…In a murine lung cancer model where the oncogenic K‐Ras G12D is expressed at the lung epithelium, accumulation of Th17 cells in the lung tumors was observed . The Ras‐GTPase inhibitor FTS suppressed the differentiation of Th17 cells and the expression of Th17‐associated IL‐17 and IL‐22 . These studies, together with the current one, suggest that Ras signaling might be critical to the development of Th17 cells and the Th17/Treg cell imbalance.…”

“…Ras‐GTPases are key switches that act downstream of the CD3/CD28 signaling and have critical roles in many cellular processes, such as mobilization, differentiation, proliferation and apoptosis . Excessive Ras signaling was shown to associate with excessive Th17 responses in autoimmune diseases . Therefore, we examined the expression of Ras in CD4 + T cells from COPD‐PH patients and controls.…”

Genetic Signatures From RNA Sequencing of Pediatric Localized Scleroderma Skin

“…The abundance of Tregs and TH17 cells has been contested in recent publications, but the consensus is that both of these cell types are decreased in LS but with an overall increase in interferon expression (all interferon subtypes). Overexpression of the KRAS signaling pathway has been shown to be critical to the development of Th17 cells and the Th17/Treg cell imbalance (45). The KRAS pathway is thought to induce the IRF7 signaling that leads to increased gene expression and induction of key proteins involved in expression and secretion of interferon gene expression inducing the conversion of CD4+-naïve T to Treg cells by upregulating genes that characterize Tregs, including FOXP3 (46)(47)(48).…”

CCR1 Activation Promotes Neuroinflammation Through CCR1/TPR1/ERK1/2 Signaling Pathway After Intracerebral Hemorrhage in Mice

“…Previous studies demonstrated the activation of Ras/ MEK/ERK in disease models of cerebral ischemia, oxidative stress, and neurodegenerative disease [48][49][50]. Ras/MEK/ ERK has been identified as a novel signaling molecule modulating inflammatory response in the arthritis of animal models [51]. A recent study showed that macrophages CCR1 activation promoted the release of TNF-α and IL-1β via activating Ras/MEK/ERK [19].…”