Macrophages in Rheumatoid Arthritis (RA)

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by articular destruction associated increasingly over time with co-morbidities in vascular, metabolic, bone, and psychological domains. The primary aetiopathogenesis of RA is considered to be autoimmune, comprising a pre-RA phase in which systemic immune mediators are detected, leading thereafter to clinically evident, the articular onset of 'early RA' that evolves into chronic inflammation('established RA') associated with tissue remodeling and damage. Some patients with RA may present or later develop disease manifestations in other organs, such as interstitial lung disease (ILD), pericarditis, pleural effusion, or bronchiectasis. Given this clinical heterogeneity, RA is probably a clinical syndrome that encompasses several disease subsets, each characterized by immune dysregulation.

Origins and Plasticity of Macrophages in RA Joints

Tissue-resident macrophages are seeded during the prenatal period from embryonic precursors in two sequential waves. The first depends on erythro-myeloid progenitors (EMPs) that develop into yolk sac-derived macrophages without a monocytic intermediate whereas the second involves fetal liver monocytes generated from late yolk sac-derived EMPs. Postnatally, macrophages are mostly derived from hematopoietic stem cells from the bone marrow which give rise to monocytes that seed the blood and tissues continuously throughout life. Healthy synovium thus contains both fetal and bone marrow-derived macrophages which maintain synovial homeostasis under steady-state. In RA, blood monocytes are recruited to the synovial joint and differentiate into monocyte-derived macrophages (moMΦ) of diverse phenotypes and monocyte-derived DCs (moDC) which are shaped towards an overall pro-inflammatory activity as a result of the altered local cytokine milieu.

Fig.1 Origins and plasticity of macrophages in RA joints. (Es, 2019)

Macrophage Polarization in RA

Studies indicate that M1 macrophages are dominant in the RA synovium and its fluid. In detail, Some studies confirm that RA synovial fluid highly expresses M1 macrophage markers, including CD40, CD80, CD86, and CD276. The markers of M1 macrophages including CD86, CD64, and CCR5 are highly expressed in mononuclear macrophages in peripheral blood of RA patients, while the marker of M2 macrophages CD163 shows low expression, and CD200R and CD16 show no difference. M1 macrophages are entwined with high levels of interleukin-1 (IL-1), IL-6, IL-23, and tumor necrosis factor (TNFα) pro-inflammatory cytokines whereas M2-linked IL-10 production is relatively diminished in patients with RA compared to healthy individuals. Indeed, RA patients display an increased M1/M2 ratio which promotes osteoclastogenesis while patients with clinical remission of RA indicate an M2-like phenotype.

Therapeutics of Targeting Macrophages in RA

No therapy has yet been shown to be efficacious and safe for the specific elimination of inflammatory macrophages in RA. But the findings indicate that strategies that selectively targeting macrophages could have therapeutic benefits in RA.

• Reprogramming of macrophages toward M2 macrophages polarization: 1) by cytokine secretion-associated RA such as IL-34, IL-37; 2) anti-Granulocyte-macrophage colony-stimulating factor (GM-CSF)-receptor antibody.
• Depletion of M1-macrophages: by CD64-directed immunotoxin.
• Inhibiting osteoclastogenesis: 1) TNFα inhibitor drugs; 2) anti-receptor activator for nuclear factor-κB ligand (RANKL) drug; 3) targeting M-CSF receptor.
• Macrophage-derived microvesicle-coated nanoparticles (MNPs) are developed to target RA.

Fig.2 Therapeutic strategies to target monocytes/macrophages in RA. (Roberts, 2015)

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References

1. Es, A.; et al. The many facets of macrophages in rheumatoid arthritis. Biochem Pharmacol, 2019, 165:152-169.
2. Roberts, C.A.; et al. The interplay between monocytes/macrophages and CD4+ T cell subsets in Rheumatoid Arthritis. Frontiers in Immunology. 2015, 6(3):571.