Abstract
BackgroundCSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis. The objective of this study was to determine the relative contributions of CSF-1 and IL-34 signaling to CSF1R in RA.MethodsCSF-1 and IL-34 were detected by immunohistochemical and digital image analysis in synovial tissue from 15 biological-naïve rheumatoid arthritis (RA) , 15 psoriatic arthritis (PsA) and 7 osteoarthritis (OA) patients . Gene expression in CSF-1- and IL-34-differentiated human macrophages was assessed by FACS analysis and quantitative PCR. RA synovial explants were incubated with CSF-1, IL-34, control antibody (Ab), or neutralizing/blocking Abs targeting CSF-1, IL-34, or CSF1R. The effect of a CSF1R-blocking Ab was examined in murine collagen-induced arthritis (CIA).ResultsCSF-1 (also known as M-CSF) and IL-34 expression was similar in RA and PsA synovial tissue, but lower in controls (P < 0.05). CSF-1 expression was observed in the synovial sublining, and IL-34 in the sublining and the intimal lining layer. CSF-1 and IL-34 differentially regulated the expression of 17 of 336 inflammation-associated genes in macrophages, including chemokines, extra-cellular matrix components, and matrix metalloproteinases. Exogenous CSF-1 or IL-34, or their independent neutralization, had no effect on RA synovial explant IL-6 production. Anti-CSF1R Ab significantly reduced IL-6 and other inflammatory mediator production in RA synovial explants, and paw swelling and joint destruction in CIA.ConclusionsSimultaneous inhibition of CSF1R interactions with both CSF-1 and IL-34 suppresses inflammatory activation of RA synovial tissue and pathology in CIA, suggesting a novel therapeutic strategy for RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0973-6) contains supplementary material, which is available to authorized users.
Highlights
Colony-stimulating factors (CSF)-1 or IL-34 stimulation of colony - stimulating factor-1 receptor (CSF1R) promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis
The study was terminated on Synovial tissue expression of Colony-stimulating factor-1 (CSF-1), IL-34 and CSF1R First, we investigated the expression of CSF-1, IL-34 and CSF1R in the synovial tissue of patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA). qPCR analysis did not identify any differences between RA and PsA patients in Messenger RNA (mRNA) expression of IL-34, CSF-1, or their receptors (Fig. 1a)
While IL-34 is expressed in the synovial sublining and the intimal lining layer, CSF-1 expression was limited primarily to the IL-34 and CSF-1 induce similar but distinct gene expression patterns in human macrophages Given that IL-34 and CSF-1 localized to distinct regions of the synovium, and macrophages in RA and PsA synovial sublining and intimal lining layers display distinct phenotypic characteristics [43], we examined the influence of these two cytokines in peripheral blood from
Summary
CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis. Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the peripheral joints, leading to joint deformity and destruction [1] Synovial macrophages, through their ability to release inflammatory cytokines, matrix metalloproteinases (MMPs), chemokines, reactive oxygen and nitrogen intermediates, and prostanoids, play a central role in the pathological process of RA [2]. Granulocytemacrophage CSF (GM-CSF) plays an important role in Garcia et al Arthritis Research & Therapy (2016) 18:75 promoting the differentiation of granulocytes and macrophages from hematopoietic precursors [4] During inflammation this property of GM-CSF may be important for the sustained recruitment of immature monocytes to affected tissues [5,6,7]. The direct relevance of these findings to RA is exemplified in recent clinical trials in which a blocking Ab directed at the alpha chain of the GM-CSF receptor has demonstrated safety and efficacy [15, 16]
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