Macrophages: The Good, the Bad, and the Gluttony.

Macrophages are dynamic cells that play critical roles in the induction and resolution of sterile inflammation. In this review, we will compile and interpret recent findings on the plasticity of macrophages and how these cells contribute to the development of non-infectious inflammatory diseases, with a particular focus on allergic and autoimmune disorders. The critical roles of macrophages in the resolution of inflammation will then be examined, emphasizing the ability of macrophages to clear apoptotic immune cells. Rheumatoid arthritis (RA) is a chronic autoimmune-driven spectrum of diseases where persistent inflammation results in synovial hyperplasia and excessive immune cell accumulation, leading to remodeling and reduced function in affected joints. Macrophages are central to the pathophysiology of RA, driving episodic cycles of chronic inflammation and tissue destruction. RA patients have increased numbers of active M1 polarized pro-inflammatory macrophages and few or inactive M2 type cells. This imbalance in macrophage homeostasis is a main contributor to pro-inflammatory mediators in RA, resulting in continual activation of immune and stromal populations and accelerated tissue remodeling. Modulation of macrophage phenotype and function remains a key therapeutic goal for the treatment of this disease. Intriguingly, therapeutic intervention with glucocorticoids or other DMARDs promotes the re-polarization of M1 macrophages to an anti-inflammatory M2 phenotype; this reprogramming is dependent on metabolic changes to promote phenotypic switching. Allergic asthma is associated with Th2-polarised airway inflammation, structural remodeling of the large airways, and airway hyperresponsiveness. Macrophage polarization has a profound impact on asthma pathogenesis, as the response to allergen exposure is regulated by an intricate interplay between local immune factors including cytokines, chemokines and danger signals from neighboring cells. In the Th2-polarized environment characteristic of allergic asthma, high levels of IL-4 produced by locally infiltrating innate lymphoid cells and helper T cells promote the acquisition of an alternatively activated M2a phenotype in macrophages, with myriad effects on the local immune response and airway structure. Targeting regulators of macrophage plasticity is currently being pursued in the treatment of allergic asthma and other allergic diseases. Macrophages promote the re-balancing of pro-inflammatory responses towards pro-resolution responses and are thus central to the success of an inflammatory response. It has long been established that apoptosis supports monocyte and macrophage recruitment to sites of inflammation, facilitating subsequent corpse clearance. This drives resolution responses and mediates a phenotypic switch in the polarity of macrophages. However, the role of apoptotic cell-derived extracellular vesicles (ACdEV) in the recruitment and control of macrophage phenotype has received remarkably little attention. ACdEV are powerful mediators of intercellular communication, carrying a wealth of lipid and protein mediators that may modulate macrophage phenotype, including a cargo of active immune-modulating enzymes. The impact of such interactions may result in repair or disease in different contexts. In this review, we will discuss the origin, characterization, and activity of macrophages in sterile inflammatory diseases and the underlying mechanisms of macrophage polarization via ACdEV and apoptotic cell clearance, in order to provide new insights into therapeutic strategies that could exploit the capabilities of these agile and responsive cells.

Ross EA ，Devitt A ，Johnson JR 《Frontiers in Immunology》

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

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.

Cutolo M ，Campitiello R ，Gotelli E ，Soldano S ... -  《Frontiers in Immunology》

Macrophage polarization and allergic asthma.

Allergic asthma is associated with airway inflammation and airway hyperresponsiveness. Macrophage polarization has been shown to have a profound impact on asthma pathogenesis. On exposure to local microenvironments, recruited macrophages can be polarized into either classically activated (or M1) or alternatively activated (or M2) phenotypes. Macrophage polarization has been heavily associated with development of asthma. The process of regulation of macrophage polarization involves an intricate interplay between various cytokines, chemokines, transcriptional factors, and immune-regulatory cells. Different signals from the microenvironment are controlled by different receptors on the macrophages to initiate various macrophage polarization pathways. Most importantly, there is an increased attention on the epigenetic changes (eg, microRNAs, DNA methylation, and histone modification) that impact macrophage functional responses and M1/M2 polarization through modulating cellular signaling and signature gene expression. Thus, modulation of macrophage phenotypes through molecular intervention by targeting some of those potential macrophage regulators may have therapeutic potential in the treatment of allergic asthma and other allergic diseases. In this review, we will discuss the origin of macrophages, characterization of macrophages, macrophage polarization in asthma, and the underlying mechanisms regarding allergen-induced macrophage polarization with emphasis on the regulation of epigenetics, which will provide new insights into the therapeutic strategy for asthma.

Saradna A ，Do DC ，Kumar S ，Fu QL ，Gao P ... -  《-》

Immunomodulatory effects of curcumin on macrophage polarization in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage destruction, pannus formation and bone erosion. Various immune cells, including macrophages, are involved in RA pathogenesis. The heterogeneity and plasticity of macrophages render them pivotal regulators of both the induction and resolution of the inflammatory response. Predominantly, two different phenotypes of macrophages have been identified: classically activated M1 macrophages exacerbate inflammation via the production of cytokines, chemokines and other inflammatory mediators, while alternatively activated M2 macrophages inhibit inflammation and facilitate tissue repair. An imbalance in the M1/M2 macrophage ratio is critical during the initiation and progression of RA. Macrophage polarization is modulated by various transcription factors, epigenetic elements and metabolic reprogramming. Curcumin, an active component of turmeric, exhibits potent immunomodulatory effects and is administered in the treatment of multiple autoimmune diseases, including RA. The regulation of macrophage polarization and subsequent cytokine production as well as macrophage migration is involved in the mechanisms underlying the therapeutic effect of curcumin on RA. In this review, we summarize the underlying mechanisms by which curcumin modulates macrophage function and polarization in the context of RA to provide evidence for the clinical application of curcumin in RA treatment.

Deng T ，Xu J ，Wang Q ，Wang X ，Jiao Y ，Cao X ，Geng Q ，Zhang M ，Zhao L ，Xiao C ... -  《Frontiers in Pharmacology》

Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key effector cells that play a central role in RA pathogenesis through their ability to polarize into distinct functional phenotypes. An imbalance favoring pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages disrupts immune homeostasis and exacerbates joint inflammation. Multiple signaling pathways, including Notch, JAK/STAT, NF-κb, and MAPK, regulate macrophage polarization towards the M1 phenotype in RA. Metabolic reprogramming also contributes to this process, with M1 macrophages prioritizing glycolysis while M2 macrophages utilize oxidative phosphorylation. Redressing this imbalance by modulating macrophage polarization and metabolic state represents a promising therapeutic strategy. Furthermore, complex bidirectional interactions exist between synovial macrophages and fibroblast-like synoviocytes (FLS), forming a self-perpetuating inflammatory loop. Macrophage-derived factors promote aggressive phenotypes in FLS, while FLS-secreted mediators contribute to aberrant macrophage activation. Elucidating the signaling networks governing macrophage polarization, metabolic adaptations, and crosstalk with FLS is crucial to developing targeted therapies that can restore immune homeostasis and mitigate joint pathology in RA.

Zheng Y ，Wei K ，Jiang P ，Zhao J ，Shan Y ，Shi Y ，Zhao F ，Chang C ，Li Y ，Zhou M ，Lv X ，Guo S ，He D ... -  《Frontiers in Immunology》