Proinflammatory Differentiation of Macrophages Through Microparticles That Form Immune Complexes Leads to T- and B-Cell Activation in Systemic Autoimmune Diseases.

Catalina Burbano,Mauricio Rojas,Diana Castaño,Gloria Vásquez,Carlos Muñoz-Vahos,Juan Villar-Vesga

doi:10.3389/fimmu.2019.02058

Catalina Burbano, Mauricio Rojas + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2019.02058

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Abstract

Patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) demonstrate increased circulating microparticles (MP). These vesicles, primarily those that form immune complexes (MP-IC), may activate monocytes. We evaluated the effect of MP and MP-IC in the differentiation of monocytes to macrophages (monocyte-derived macrophages; MDM) and for consequences in autologous lymphocyte activation. Monocytes from healthy controls (HC) and patients with RA and SLE that differentiated into MDM in the presence of MP-IC showed a proinflammatory (M1-like) profile, which was more evident using MP-IC from patients with RA than those from patients with SLE. Notably, MDM from HC and patients with RA that differentiated with MP-IC were more prone to M1-like profile than those from patients with SLE. In HC and patients with RA, monocyte differentiation using MP-IC decreased the frequency of MDM that bound/internalized latex beads. The M1-like profile did not completely revert following IL-4 treatment. The effect of M1-like MDM on T lymphocytes stimulated with phytohemagglutinin was further evaluated. MDM differentiated with MP enhanced the proliferation of T cells obtained from patients with RA compared with those differentiated with MP-IC or without vesicles. Neither MP nor MP-IC induced interferon (IFN)-γ+ and tumor necrosis factor (TNF)-α+ T cells in patients with RA. Conversely, unlike MDM differentiated with or without MP, MP-IC enhanced the proliferation and increased the frequencies of IFN-γ+CD4+ T, TNF-α+CD4+ T, and IFN-γ+CD8+ T cells in patients with SLE. The co-culture of B cells with MDM obtained from patients with RA and SLE and differentiated with MP-IC increased the expression of B-cell activation markers and prevented B lymphocyte death. Strikingly, only for patients with SLE, these responses seemed to be associated with a significant increase in B-cell activating factor levels, high plasmablast frequency and immunoglobulin production. These results showed that MP-IC from patients with systemic autoimmune diseases favored the polarization of MDM into a proinflammatory profile that promotes T-cell activation, and additionally induced B-cell activation and survival. Therefore, the effect of MP-IC in mononuclear phagocytes may be an important factor for modulating adaptive responses in systemic autoimmune diseases.

Highlights

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic systemic autoimmune diseases affecting a large number of people globally [1]
We propose that circulating MP, and especially MP-immune complex (IC), of patients with SLE and RA can directly alter the differentiation of monocytes into proinflammatory macrophages, contributing to the amplification, and perpetuation of autoimmune phenomena and chronic inflammation in affected tissues
The effect of MP and MP-IC in monocyte-derived macrophages (MDM), regarding changes in morphology, the expression of differentiation (HLA-DR, CD16, CD14, CCR2, and CD36) and activation (CD86, CD80, Toll-like receptors (TLR)-4, CD163, and CD209) markers and the expression of cytokine levels (IL-1β, IL-6, TNFα, IL-10, IL-8, and IL12p70) were evaluated in mononuclear phagocytes obtained from healthy controls (HC) and patients with RA and SLE, differentiated without (MDM-Unstimulated, -Unstim) or with extracellular vesicles (MP from SLE: MDM-LMP and MDM-LMP-IC; MP from RA: MDM-RMP and MDM-RMPIC)

Summary

Introduction

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic systemic autoimmune diseases affecting a large number of people globally [1]. The etiology of SLE and RA is not completely known; both diseases are characterized by the presence of antibodies against selfantigens [2, 3] These autoantibodies have been associated with a loss of central and peripheral mechanisms of tolerance, as well as with tissue damage and the maintenance of chronic inflammatory responses, through immune complex (IC) formation, recognition and tissue deposits [2, 3]. Extracellular vesicles such as microparticles (MP) were reported as one of the main sources of circulating IC in RA and SLE [4,5,6]. MP-IC seem to signal mononuclear phagocytes via Fcγ and complement receptors, perpetuating the inflammatory process in these patients [11, 12]

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