Synovial MS4A4A correlates with inflammation and counteracts response to corticosteroids in arthritis

• 成果类型: Article
• 署名作者: Boutet, Marie-Astrid; Mattiola, Irene; Silva-Gomes, Rita; Nerviani, Alessandra; Sironi, Marina; Ghirardi, Giulia Maria; Troilo, Alessia; Gianoli, Stefano; Rivellese, Felice; Cubuk, Cankut; Goldmann, Katriona; Putignano, Anna Rita; Di Silvestre, Dario; Lomagno, Andrea; Borroni, Elena Monica; Sobacchi, Cristina; Lewis, Myles J.; Bottazzi, Barbara; Locati, Massimo; Mantovani, Alberto; Pitzalis, Costantino
• 署名单位: University of London; Queen Mary University London; University of London; Queen Mary University London; Nantes Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Ecole Nationale Veterinaire, Agroalimentaire et de l'Alimentation Nantes-Atlantique; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Universidade do Minho; University of Milan; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Consiglio Nazionale delle Ricerche (CNR); Istituto di Tecnologie Biomediche (ITB-CNR); Consiglio Nazionale delle Ricerche (CNR); Istituto di Ricerca Genetica e Biomedica (IRGB-CNR); Humanitas University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10750
• DOI: 10.1073/pnas.2504529122
• 发表日期: 2025-09-16
• 关键词: rheumatoid-arthritis; macrophages; expression; generation; rituximab; biomarker; immunity; biopsy; FAMILY; tissue

摘要

MS4A4A belongs to the MS4A tetraspan protein superfamily and is selectively expressed by the monocyte-macrophage lineage. In this study, we aimed to evaluate the role of MS4A4A+ macrophages in rheumatoid arthritis (RA) pathogenesis and response to treatment. RNA sequencing and immunohistochemistry of synovial samples from either early treatment-na & iuml;ve or active chronic RA patients showed that MS4A4A expression positively correlated with synovial inflammation. Synovial macrophages from patients treated with corticosteroids (CS) exhibited an enhanced expression of MS4A4A and Fc gamma receptor (Fc gamma R) 3. Accordingly, CS enhanced in vitro the expression of MS4A4A and Fc gamma R3 in human and murine macrophages. In an experimental model of arthritis, Ms4a4a deletion had no effect on the disease course but was associated with enhanced therapeutic response selectively to CS. These results suggest that macrophage expression of MS4A4A represents a biomarker of joint inflammation in RA and that its upregulation in concert with Fc gamma R3 by CS counteracts the therapeutic activity of these drugs. Macrophage MS4A4A may represent a biomarker of joint inflammation in RA and a target to amplify the therapeutic activity of CS.