Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium

Abstract

Objectives Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. Methods CD4+ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. Results Semaphorin 3G expression in CD4+ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. Conclusions Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.

The relationship of ALPK1, hyaluronic acid and M1 macrophage polarization in the temporomandibular joint synovitis

“…At present, studies have confirmed that ALPK1 is a promoting factor in several inflammation‐related diseases 11,12 . Meanwhile, M1 macrophage polarization plays an important role in the development of joint inflammation 37 . Moreover, M1 macrophages play a more critical role in cartilage damage in TMJOA patients than other common cell populations 38 .…”

“… 11 , 12 Meanwhile, M1 macrophage polarization plays an important role in the development of joint inflammation. 37 Moreover, M1 macrophages play a more critical role in cartilage damage in TMJOA patients than other common cell populations. 38 Inhibition of M1 macrophage polarization alleviates TMJOA.…”

TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis

“…To identify genes whose expression in CD4 + T cells is regulated by MTX, we examined comprehensive gene expression profiles of CD4 + T cells of patients with RA before and after MTX treatment, using DNA microarray analysis. We identified several differentially expressed genes (DEGs), as described previously ( 21 ). In this study, we focused on TP63 because it showed a maximum reduction in signal intensity following MTX treatment ( Figure 1A and Table 1 ).…”

“…Patients. Patients who fulfilled the American College of Rheumatology 1987 revised criteria for the classification of RA and received MTX therapy as a first antirheumatic drug were consecutively recruited at Chiba University Hospital and Asahi General Hospital, as described previously (21). Patients with RA who received treatment with biologic antirheumatic drugs (TNF antagonists, TCZ, or ABT) were also recruited as controls.…”

“…Patients received routine clinical care and underwent clinical and laboratory assessment, which included 28-joint counts for swelling and tenderness, patient's and physician's global assessment of disease activity on a visual analog scale, erythrocyte sedimentation rate (ESR), and serum C-reactive (CRP) protein levels, at baseline and 3 months after the treatment. Patients' characteristics and disease activity are listed in Table 2 (21). JCI Insight 2023;8(10):e164778 https://doi.org/10.1172/jci.insight.164778 DNA microarray analysis.…”