Synovial MS4A4A correlates with inflammation and counteracts response to corticosteroids in arthritis
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-naïve 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 γ receptor (FcγR) 3. Accordingly, CS enhanced in vitro the expression of MS4A4A and FcγR3 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 FcγR3 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.
Authors
- Rita Silva-Gomes (ORCID: https://orcid.org/0000-0003-1529-3777)
- Katriona Goldmann (ORCID: https://orcid.org/0000-0002-9073-6323)
- Arianna Troilo (ORCID: https://orcid.org/0000-0001-7229-3058)
- Alessandra Nerviani (ORCID: https://orcid.org/0000-0003-4064-4014)
- Massimo Locati (ORCID: https://orcid.org/0000-0003-3077-590X)
- Anna Rita Putignano (ORCID: https://orcid.org/0000-0002-6462-9188)
- Dario Di Silvestre (ORCID: https://orcid.org/0000-0002-7143-6229)
- Felice Rivellese (ORCID: https://orcid.org/0000-0002-6759-7521)
- Alberto Mantovani (ORCID: https://orcid.org/0000-0001-5578-236X)
- Giulia Maria Ghirardi (ORCID: https://orcid.org/0000-0002-4176-2031)
- Myles Lewis (ORCID: https://orcid.org/0000-0001-9365-5345)
- Costantino Pitzalis (ORCID: https://orcid.org/0000-0003-1326-5051)
- Cristina Sobacchi (ORCID: https://orcid.org/0000-0002-2684-7184)
- Elena Monica Borroni (ORCID: https://orcid.org/0000-0003-1157-8249)
- Barbara Bottazzi (ORCID: https://orcid.org/0000-0002-1930-9257)
- Marie‐Astrid Boutet (ORCID: https://orcid.org/0000-0002-1519-6902)
- Irene Mattiola (ORCID: https://orcid.org/0000-0002-2922-9947)
- Marina Sironi (ORCID: https://orcid.org/0000-0002-3342-1149)
- Cankut Çubuk (ORCID: https://orcid.org/0000-0003-4646-0849)
- Stefano Gianoli (ORCID: https://orcid.org/0000-0001-6857-3305)
- Andrea Lomagno (ORCID: https://orcid.org/0009-0007-5807-7827)
Institutions
- Boston Children's Hospital (US)
- Humanitas University (IT)
- Inserm (FR)
- Queen Mary University of London (GB)
- University of Milan (IT)
- Abterra Biosciences (United States) (US)
- Proteogenomics Research Institute for Systems Medicine (US)
- Institute of Genetic and Biomedical Research (IT)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- William Harvey Research Institute (GB)
- Center for Pain and the Brain (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Institute of Biomedical Technologies (IT)
- National Research Council (IT)
- Institute of Polymers, Composites and Biomaterials (IT)
- IRCCS Humanitas Research Hospital (IT)
- Franklin University (US)
- Nantes Université (FR)
- University of Minho (PT)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-09-09
- DOI
- https://doi.org/10.1073/pnas.2504529122
- Primary Topic
- Rheumatoid Arthritis Research and Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Queen Mary University of London
- Università degli Studi di Milano
- National Institute for Health and Care Research
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Associazione Italiana per la Ricerca sul Cancro
- European League Against Rheumatism
- Universidade do Minho
- Humanitas University
- Versus Arthritis
- European Federation of Immunological Societies
- Berlin Institute of Health
- Humanitas Research Hospital
- Medical Research Council
- Fundação para a Ciência e a Tecnologia