OBJECTIVE: Cells of the monocytic lineage play fundamental roles in the regulation of health, ranging from the initiation and resolution of inflammation to bone homeostasis. In rheumatoid arthritis (RA), the inflamed synovium exhibits characteristic infiltration of macrophages along with local osteoclast maturation, which, together, drive chronic inflammation and downstream articular destruction. The aim of this study was to explore an entirely novel route of immunoglobulin-mediated regulation, involving simultaneous suppression of the inflammatory and erosive processes in the synovium. METHODS: Using in vivo and in vitro studies of human cells and a murine model of RA, the ability of staphylococcal protein A (SPA) to interact with and modulate cells of the monocytic lineage was tested. In addition, the efficacy of SPA as a therapeutic agent was evaluated in murine collagen-induced arthritis (CIA). RESULTS: SPA showed a capacity to appropriate circulating IgG, by generating small immunoglobulin complexes that interacted with monocytes, macrophages, and preosteoclasts. Formation of these complexes resulted in Fcγ receptor type I-dependent polarization of macrophages to a regulatory phenotype, rendering them unresponsive to activators such as interferon-γ. The antiinflammatory complexes also had the capacity to directly inhibit differentiation of preosteoclasts into osteoclasts in humans. Moreover, administration of SPA in the early stages of disease substantially alleviated the clinical and histologic erosive features of CIA in mice. CONCLUSION: These findings demonstrate the overarching utility of immunoglobulin complexes for the prevention and treatment of inflammatory diseases. The results shed light on the interface between immunoglobulin complex-mediated pathways, osteoclastogenesis, and associated pathologic processes. Thus, therapeutic agents designed to harness all of these properties may be an effective treatment for arthritis, by targeting both the innate inflammatory response and prodestructive pathways.
OBJECTIVE: Cells of the monocytic lineage play fundamental roles in the regulation of health, ranging from the initiation and resolution of inflammation to bone homeostasis. In rheumatoid arthritis (RA), the inflamed synovium exhibits characteristic infiltration of macrophages along with local osteoclast maturation, which, together, drive chronic inflammation and downstream articular destruction. The aim of this study was to explore an entirely novel route of immunoglobulin-mediated regulation, involving simultaneous suppression of the inflammatory and erosive processes in the synovium. METHODS: Using in vivo and in vitro studies of human cells and a murine model of RA, the ability of staphylococcal protein A (SPA) to interact with and modulate cells of the monocytic lineage was tested. In addition, the efficacy of SPA as a therapeutic agent was evaluated in murine collagen-induced arthritis (CIA). RESULTS: SPA showed a capacity to appropriate circulating IgG, by generating small immunoglobulin complexes that interacted with monocytes, macrophages, and preosteoclasts. Formation of these complexes resulted in Fcγ receptor type I-dependent polarization of macrophages to a regulatory phenotype, rendering them unresponsive to activators such as interferon-γ. The antiinflammatory complexes also had the capacity to directly inhibit differentiation of preosteoclasts into osteoclasts in humans. Moreover, administration of SPA in the early stages of disease substantially alleviated the clinical and histologic erosive features of CIA in mice. CONCLUSION: These findings demonstrate the overarching utility of immunoglobulin complexes for the prevention and treatment of inflammatory diseases. The results shed light on the interface between immunoglobulin complex-mediated pathways, osteoclastogenesis, and associated pathologic processes. Thus, therapeutic agents designed to harness all of these properties may be an effective treatment for arthritis, by targeting both the innate inflammatory response and prodestructive pathways.
Authors: Nikolett Marton; Orsolya Tünde Kovács; Eszter Baricza; Ágnes Kittel; Dávid Győri; Attila Mócsai; Florian M P Meier; Carl S Goodyear; Iain B McInnes; Edit I Buzás; György Nagy Journal: Cell Mol Life Sci Date: 2017-05-10 Impact factor: 9.261
Authors: Kyung-Hyun Park-Min; Eun Young Lee; Neal K Moskowitz; Elisha Lim; Sun-Kyeong Lee; Joseph A Lorenzo; Chuanxin Huang; Ari M Melnick; P Edward Purdue; Steven R Goldring; Lionel B Ivashkiv Journal: J Bone Miner Res Date: 2013-01 Impact factor: 6.741
Authors: Ulrike Harre; Stefanie C Lang; René Pfeifle; Yoann Rombouts; Sabine Frühbeißer; Khaled Amara; Holger Bang; Anja Lux; Carolien A Koeleman; Wolfgang Baum; Katharina Dietel; Franziska Gröhn; Vivianne Malmström; Lars Klareskog; Gerhard Krönke; Roland Kocijan; Falk Nimmerjahn; René E M Toes; Martin Herrmann; Hans Ulrich Scherer; Georg Schett Journal: Nat Commun Date: 2015-03-31 Impact factor: 14.919
Authors: Chris A H Hansell; Lindsay M MacLellan; Rachel S Oldham; James Doonan; Katie J Chapple; Elinor J R Anderson; Christopher Linington; Iain B McInnes; Robert J B Nibbs; Carl S Goodyear Journal: Immunol Cell Biol Date: 2014-10-28 Impact factor: 5.126