The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis

Abstract

Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.

Sympathectomy Ameliorates CFA-Induced Mechanical Allodynia via Modulating Phenotype of Macrophages in Sensory Ganglion in Mice

“…As previously studies have found that macrophage with distinct functional infiltrated in the sensory ganglion is important for the maintenance and resolution of pain, [51][52][53] we thereafter detected two genes, CD86 and CD163-two annotated markers that represent distinct functional outcomes in the course of inflammatory pain. 54 We found that orofacial inflammation caused a significant increase in both M1 and M2 infiltration in the TG at early days, but the proportion of M2 was significantly lower than that of M1 for 2 weeks in the CFA model. We observed the ratio of M1/M2 was relatively high during the early phases, whereas macrophage transit from a M1-like phenotype to M2 at later time points.…”

Immune Effects of Macrophages in Rheumatoid Arthritis: A Bibliometric Analysis From 2000 to 2021

“…In patients with RA, the abnormal immune microenvironment promotes metabolic reprogramming, alters macrophage polarization states, disrupts the dynamic balance of M1 and M2 macrophages, and delays tissue inflammation. Aa a result, inhibiting M1 macrophage polarization and inducing M2 macrophage polarization are ideal drug research and development strategies in the treatment of RA ( 30 , 31 ).…”

Aromatase Inhibitor Induced Musculoskeletal Inflammation is Observed Independent of Oophorectomy in a Novel Mouse Model

“…Additionally, therapeutic strategies leveraging selective macrophage phagocytosis of lipid particles loaded with immunomodulatory biocargo should also be considered [24] (similar to our strategy used in curcumin-containing lipid nanoparticles [21]). In addition to these potential interventions, the use of disease-modifying antirheumatic drugs (DMARDs) that have demonstrated the capacity to drive macrophage polarization from the pro-inflammatory M1 state to the wound healing M2 state may also be effective treatments for AIIA [25]. Specifically, Abatacept (small molecule inhibitor that blocks T cell activation by binding to CD80 or CD86 extracellularly to prevent interaction with co-stimulatory receptor CD28), Etanercept (soluble TNF receptor that competitively binds TNF-α and TNF-β), Infliximab (mAb that binds to TNF-α), Rituximab (mAb that binds to CD20 and inhibits B cell activation), and Tocilizumab (anti-IL-6 mAb) are all DMARDs to consider in future studies evaluating the efficacy of preventing or treating AIIA.…”