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.

Keywords: Inflammation; Macrophage polarization; Rheumatoid anhritis; Synovitis; bDMARD therapy.

Figure 1

Monocyte differentiation and related role in RA pathogenesis. Differentiation of circulating monocytes in their three subsets, classical (CD14^high), intermediate (CD14^highCD16^high), and non-classical (CD14^dimCD16^high) monocytes. Classical monocytes can differentiate into pro-inflammatory macrophages and osteoclasts, contributing to synovial tissue inflammation and bone erosion; intermediate monocytes differentiate into pro-inflammatory macrophages contributing to tissue inflammation; non-classical monocytes differentiate into anti-inflammatory macrophages promoting phagocytosis and resolution of inflammation.

Figure 2

Representation of acute RA inflammation and remission. Acute RA inflammatory phase is characterized by an imbalance in M1–M2 ratio in synovial fluid and tissue. This phase is dominated by a higher percentage of pro-inflammatory M1 macrophages, which display specific phenotype markers and release cytokines/chemokines. Moreover, the activation of osteoclasts contributes to bone erosion. RA disease remission is characterized by a high percentage of anti-inflammatory M2 macrophages, which display specific phenotype markers and release anti-inflammatory cytokines/chemokines.

Figure 3

Intracellular signaling and metabolic pathways activated into RA anti-inflammatory M2 macrophages. Metabolic pathways activated in M2 macrophages that contribute to their anti-inflammatory role in RA. NFkB, nuclear factor-kB; SIRT1, sirtuin-1; AMPK, adenosine monophosphate-activated protein kinase; IL-10, interleukine-10; IL-12, interleukine-12; TGFβ1, transforming growth factor-β1; NO, nitric oxide; CD206, mannose receptor-1; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine.

Figure 4

Intracellular signaling and metabolic pathways activated into RA pro-inflammatory M1 macrophages. Intracellular signaling and metabolic pathways activated in M1 macrophages that contribute to their pro-inflammatory role in the inflammatory process in RA. TLR4, Toll-like receptor 4; IL-6R, interleukine-6 receptor; IL-1βR, interleukine-1β receptor; TNFR, tumor necrosis factor receptor; NFkB, nuclear factor-kB; SAPK: stress-activated protein kinases; MAPK, mitogen-activated protein kinases; JAK, Janus kinase; STAT, signal transducer and activators of transcription; Erk1/2, extracellular signal-regulated protein kinases 1 and 2; JNK, Jun N-terminal kinase; TFs, transcription factors; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; HIF-1α, hypoxia-inducible factor-1α; ROS, reactive oxygen species; /, break in Krebs cycle.