Abstract
Macrophages contribute to the pathogenesis of rheumatoid arthritis (RA). They can display different states of activation or “polarization,” notably the so-called inflammatory “M1” and the various alternative “M2” polarizations, characterized by distinct functions. Data regarding the effects of RA anti-cytokine biological disease-modifying anti-rheumatic drugs (bDMARDs) on macrophage polarization are scarce. We aimed to assess in vitro modulation of macrophage polarization by bDMARDs targeting pro-inflammatory cytokines in RA. We generated monocyte derived macrophages using blood samples from 20 RA patients with active RA and 30 healthy controls. We evaluated in vitro the impact on M1 inflammatory macrophages of: etanercept (ETA), adalimumab (ADA), certolizumab (CZP), tocilizumab (TCZ), and rituximab (RTX). We assessed the impact on macrophage polarization using flow cytometry and RTqPCR to study the expression of surface markers and perform functional studies of cytokine production, phagocytosis, and negative feedback control of inflammation. Among evaluated bDMARDs, anti-TNF agents modulated the polarization of inflammatory macrophages by decreasing inflammatory surface markers (CD40, CD80) and favoring alternative markers (CD16, CD163, MerTK). Anti-TNF agents also induced alternative functions in macrophages activated in inflammatory condition with (i) the inhibition of inflammatory cytokines (TNF, IL-6, IL-12), (ii) an increase in phagocytosis. These findings were mechanistically related to an increase in early IL-10 production, responsible for higher negative feedback control of inflammation involving SOCS3 and Gas6. This IL-10 effect was STAT3-dependent. Anti-TNF agents not only inhibit in vitro inflammatory functions of macrophages, but also favor resolution of inflammation through polarization toward alternative features specifically involving the IL-10/STAT3 axis.
Highlights
Plasticity is a key feature of macrophages
Given that IL-10 is involved in the impact of anti-TNF agents on polarization, and that STAT3 is a key transcription factor in M(IL10) commitment, we evaluated the implication of STAT3 in the modulation of macrophage polarization induced by antiTNF agents in an M1 inflammatory context
This study demonstrates that anti-TNF agents downregulate surface markers and cytokines associated with an inflammatory phenotype in macrophages, and favor properties such as phagocytosis and negative feedback of inflammation supporting the resolution of inflammation through an IL-10/STAT3 pathway
Summary
Plasticity is a key feature of macrophages They can be activated by many stimuli, depending on their environment, resulting in specific states of polarization. Macrophages play a central effector role in rheumatoid synovitis They contribute to the inflammatory environment: by producing pro-inflammatory cytokines, especially TNF [7], by enhancing synovial homing of immune cells through chemokines (CCL2, CCL3, CCL5, IL-8, CX3CL1) [8], by producing angiogenic factors (Vascular Endothelial Growth Factor, Fibroblast Growth Factor-β, Platelet-Derived Growth Factor) [9,10,11,12], and by inducing oxidative damage through reactive oxygen species [13]. In addition to their welldescribed role in the effector phase of RA, macrophages may contribute to the disease onset, especially by generating arthritogenic citrullinated peptides [18, 19]
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