Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

Abstract

Monocytes/macrophages play a central role in chronic inflammatory disorders, including rheumatoid arthritis (RA). Activation of these cells results in the production of various mediators responsible for inflammation and RA pathogenesis. On the other hand, the depletion of macrophages using specific antibodies or chemical agents can prevent their synovial tissue infiltration and subsequently attenuates inflammation. Their plasticity is a major feature that helps the switch from a pro-inflammatory phenotype (M1) to an anti-inflammatory state (M2). Therefore, understanding the precise strategy targeting pro-inflammatory monocytes/macrophages should be a powerful way of inhibiting chronic inflammation and bone erosion. In this review, we demonstrate potential consequences of different epigenetic regulations on inflammatory cytokines production by monocytes. In addition, we present unique profiles of monocytes/macrophages contributing to identification of new biomarkers of disease activity or predicting treatment response in RA. We also outline novel approaches of tuning monocytes/macrophages by biologic drugs, small molecules or by other therapeutic modalities to reduce arthritis. Finally, the importance of cellular heterogeneity of monocytes/macrophages is highlighted by single-cell technologies, which leads to the design of cell-specific therapeutic protocols for personalized medicine in RA in the future.

Keywords: biologics; biomarkers; epigenetics; heterogeneity; macrophages; monocytes; personalized therapy; rheumatoid arthritis; single-cell sequencing; small molecules.

Figure 1

Schematic representation of macrophage polarization and its various stimuli differentiating toward pro- or anti-inflammatory phenotypes in RA. On the left side, monocytes can differentiate toward pro-inflammatory M1 macrophages, osteoclasts and inflammatory DCs (InfDCs); on the right side, monocytes can differentiate toward anti-inflammatory M2 macrophages and tolerogenic DCs (TolDCs).

Figure 2

Schematic representation of differences between the RA joint (right) and a healthy joint (left). Monocytes/macrophages are the main producers of the pro-inflammatory cytokines that cause arthritis, cartilage destruction and bone loss in the RA joint. Involved in arthritis are also neutrophils, B cells, T cells, dendritic cells and osteoclasts. The synovial membrane is formed by a lining layer and a sublining layer. The lining layer it is made up of MLS (macrophage-like synovial cells) and FLS (fibroblast cells). Non-resident macrophages that arise from monocytes enter the joint from blood vessels.

Figure 3

Modulation of macrophage in RA. Activated macrophages produce pro-inflammatory molecules which can be neutralized by monoclonal antibodies or inhibited by chemical agents and oligonucleotides.