Synovial MS4A4A correlates with inflammation and counteracts response to corticosteroids in arthritis
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Marie-Astrid Boutet
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Irene Mattiola
Institute of Microbiology, Infectious Diseases and Immunology (I-MIDI), Charité-Universitätsmedizin Berlin Campus Benjamin Franklin
Rita Silva-Gomes
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Alessandra Nerviani
Marina Sironi
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Giulia Maria Ghirardi
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Alessia Troilo
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Stefano Gianoli
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Felice Rivellese
Cankut Cubuk
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Katriona Goldmann
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Anna Rita Putignano
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Dario Di Silvestre
Clinical Proteomics Laboratory, Institute for Biomedical Technologies
Andrea Lomagno
Clinical Proteomics Laboratory, Institute for Biomedical Technologies
Elena Monica Borroni
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Cristina Sobacchi
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Myles J. Lewis
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Barbara Bottazzi
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Massimo Locati
Cellular and Humoral Innate Immunity Lab, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Alberto Mantovani
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Costantino Pitzalis