Exploring the Role of Macrophages and Their Associated Structures in Rheumatoid Arthritis

Abstract

Background: Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.

Summary: This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.

Key messages: During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function in RA.

Background: Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.

Summary: This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.

Key messages: During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function in RA.

Keywords: Macrophage exosome; Macrophage extracellular traps; Macrophage polarization; Macrophage pyroptosis; Rheumatoid arthritis.

Fig. 1.

Healthy joints versus RA (by Figdraw). In RA, the immune barrier formed by a high concentration of tissue-resident macrophages in the synovial endothelial layer is disrupted compared with healthy joints, leading to continuous invasion of synovial fibroblasts in the endothelial layer into the intra-articular space, as well as infiltration of pathogenic fibroblasts, macrophages, and other inflammatory cells in the sublining layer, resulting in synovial inflammation, which leads to narrowing of the joint space, cartilage destruction, and bone erosion.

Fig. 2.

RA pathogenesis (by Figdraw). (1) T lymphocytes: These include Th1, which produces IFN-γ and TNF-α, and Th17, which produces IL-17 and IL-22 and stimulates the expression of RANKL, which activates synovial macrophages and synovial fibroblasts. In addition, T lymphocytes activate B lymphocytes via the receptor TCR and the major histocompatibility complex (MHC). (2) B lymphocytes: Activated B cells differentiate into plasma cells that produce RA autoantibodies (e.g., ACPA, rheumatoid factor [RF]), and these autoantibodies further drive the inflammatory and immune responses through the complement cascade. In addition to producing autoantibodies, B lymphocytes secrete a variety of cytokines to promote inflammation and increase RANKL expression to activate OCs. (3) Synovial macrophages: Synovial macrophages secrete a large number of strong proinflammatory cytokines, TNF-α, IL-1β, IL-6, and ROS, which contribute to the establishment and maintenance of an inflammatory environment in the synovium. In addition, macrophages induce neutrophil apoptosis and play a role in removing neutrophil load. Macrophages also have interactions with synovial fibroblasts. (4) Synovial fibroblasts: Synovial fibroblasts produce large amounts of the matrix protease MMP and stimulate the expression of RANKL to increase OC activity and maturation leading to bone erosion. (5) Neutrophils: The presence of many neutrophils in synovial fluid produces MMP and ROS, which may lead to bone erosion and cartilage degeneration.

Fig. 3.

Mechanisms and role of macrophage polarization (by Figdraw). Macrophages, upon activation by different stimuli, can differentiate into M1 (classically activated) macrophages and M2 (alternatively activated) macrophages. These two distinct phenotypes of macrophages are involved in Th1 and Th2 immune responses, respectively. M1 macrophages secrete large amounts of proinflammatory mediators, while M2 macrophages produce substantial quantities of anti-inflammatory mediators. Together, they exert opposing yet complementary effects.

Fig. 4.

Macrophage polarization-related signaling pathway (by Figdraw). (1) The JAK/STAT signaling pathway: IFN-γ binds to its receptor, activates Janus kinase (JAK), and then induces the phosphorylation of signal transducer and activator of transcription 1 (STAT1), leading to macrophage polarization to M1; however, the stimulation of IL-4 and IL-6 induces the phosphorylation of STAT6 and STAT3, respectively, which inhibits M1 polarization and promotes M2 polarization. Suppressors of cytokine signaling (SOCS) is a feedback inhibitor of the JAK/STAT signaling. Therefore, the regulation of SOCS can affect M1/M2 polarization through the JAK/STAT signaling pathway. (2) The TLR4/NF-κB signaling pathway: LPS binds to TLR4 and activates NF-κB through myeloid differentiation factor 88 (MyD88) or interferon-regulating factor 3 (IRF3), which promotes M1 polarization. (3) The TGF-β/Smad signaling pathway: TGF-β binds to its receptor, forms a receptor complex and phosphorylates it, and then activates the phosphorylation of its downstream signaling molecules (Smad2 and Smad3) to inhibit M1 polarization and promote M2 polarization. In addition to their synergistic effects, TGF-β and Smads can separately mediate macrophage polarization. (4) The Notch signaling pathway: Notch signaling is closely related to miRNAs, such as miR-125a, miR-99b, and miR-148a-3p, which are the mediators of Notch promoting M1 polarization. (5) The peroxisome proliferator-activated receptor (PPARγ) signaling pathway: PPARγ often regulates macrophage polarization by interacting with other signaling pathways. For example, PPARγ can depend on the upregulation of fatty acid oxidation, which mediates M2 polarization.

Fig. 5.

Mechanism of cellular pyroptosis (by Figdraw). One of them is the classical inflammasome pathway under the stimulation of a variety of pathogenic microorganisms, and the body detects pathogen-associated molecular patterns and damage-associated molecular patterns and recruits the assembly of inflammasome NLRP3, which then starts to recruit and activate the precursor of caspase-1 under the mediating effect of articulin ASC to become the mature, shear-functioning effector protein caspase-1. Then, caspase-1 cuts off the C-terminal end of GSDMD, a key protein for pyroptosis, and only the remaining GSDMD-N-terminal end has a pore-forming effect, which eventually localizes on the plasma membrane to form a plasma membrane pore, allowing the release of cellular contents. The second is the nonclassical inflammatory vesicle pathway, which is mediated by LPS, a cell wall component of Gram-negative bacteria, to form mature active caspase-11/4/5, which functions to cleave GSDMD. In addition to different effector protein caspases, the classical pathway process releases large amounts of inflammatory factors IL-1β and IL-18, which accelerate the inflammatory response.

Fig. 6.

Mechanism of exosome formation and its contents (by Figdraw). Exosomes originate from early endosomes formed by endocytosis of the plasma membrane, early endosomes gradually develop into late endosomes, with the entry of some “goods” in the cytoplasm, such as miRNA, proteins, etc., late endosomes will become multivesicular bodies, and part of the multivesicular bodies will be sent to the lysosomes to be lysed, and part of them will be fused with the plasma membrane to be released into the extracellular space to form exosomes. Some of them will be transferred to lysosomes to be dissolved, and some of them will be fused with the plasma membrane and released to the extracellular space to form exosomes. Exosomes contain various nucleic acids, proteins, and lipids, such as mRNA, major histocompatibility complex (MHC), transmembrane proteins, and integrins.