The high plasticity of macrophages is essential for tissue repair and regeneration, as they regulate inflammation, promote angiogenesis, and facilitate extracellular matrix remodeling, thereby restoring tissue homeostasis.
Abstract
Macrophages play a pivotal regulatory role in inflammation, tissue repair, and fibrosis through their dynamic changes in phenotype and function. The tissue microenvironment following injury induces alterations in key metabolic enzymes, signaling pathways, and metabolites within macrophages, thereby driving shifts in their phenotype and function. Early in acute injury, macrophages primarily rely on glycolysis and the pentose phosphate pathway, transitioning to a pro-inflammatory phenotype. Persistent activation of pro-inflammatory macrophages can lead to tissue damage. As the metabolic microenvironment evolves, the expression of glycolysis-related genes is suppressed, while the expression of genes related to oxidative phosphorylation and the tricarboxylic acid cycle is upregulated, promoting the gradual shift of macrophages toward an anti-inflammatory phenotype. This process plays a crucial role in tissue repair and remodeling. However, sustained activation of anti-inflammatory macrophages may contribute to the development of fibrosis. Therefore, metabolic reprogramming of macrophages presents a novel potential therapeutic target for intervening in inflammatory injury and stromal fibrosis. The high plasticity of macrophages is essential for tissue repair and regeneration, as they regulate inflammation, promote angiogenesis, and facilitate extracellular matrix remodeling, thereby restoring tissue homeostasis. This capability holds promise for the treatment of various conditions, including chronic wounds, fibrotic diseases, and inflammatory disorders.
Inflammation is a tightly regulated process essential for skeletal muscle repair, and its dysregulation contributes to chronic disease and impaired regeneration. Following injury, muscle repair involves a coordinated immune response initiated by neutrophil infiltration, followed by macrophage recruitment and diversification. Rather than existing as discrete subsets, macrophages span a continuum of functional states that evolve over time in response to local environmental cues, enabling transitions from clearing debris and pro-inflammatory signaling to supporting resolution of inflammation, and remodeling and regeneration of the tissue. This functional plasticity is closely linked to intracellular metabolic programs. In this review, we examine how metabolic pathways, particularly the balance between glycolysis and oxidative phosphorylation, govern macrophage behavior through epigenetic mechanisms, thereby coupling cellular metabolism to inflammatory and regenerative gene expression. We further explore how these interconnected pathways are disrupted in chronic inflammatory muscle diseases, including muscular dystrophies. Recent transcriptomic studies highlight pathogenic macrophage populations with altered metabolic and epigenetic profiles that contribute to fibrosis and impaired regeneration. By integrating findings from both acute injury and chronic disease contexts, we provide a framework to explore macrophage function through a metabolic and epigenetic lens and discuss emerging strategies aimed at restoring macrophage plasticity and promoting the resolution of inflammation in muscle disease.
Sarah Tiufekchiev-Grieco, James S. Novak, Jyoti K. Jaiswal· Frontiers in Immunology· 0 citations
Pulmonary macrophages are essential regulators of immune surveillance, tissue homeostasis, and inflammatory responses within the respiratory microenvironment. Emerging evidence indicates that chronic environmental stress and persistent injury induce profound immunometabolic remodeling in these cells, thereby contributing to the development and progression of chronic lung diseases. Under physiological conditions, pulmonary macrophages maintain metabolic homeostasis primarily through oxidative phosphorylation and fatty acid oxidation. However, pathological conditions drive metabolic reprogramming characterized by altered glycolysis, mitochondrial dysfunction, oxidative stress, lipid dysregulation, and disturbed iron homeostasis, leading to persistent inflammation, impaired tissue repair, and progressive remodeling. Recent studies have further highlighted the critical interplay between metabolic pathways, redox signaling, and immune regulation in shaping macrophage phenotypes and functions. Importantly, therapeutic strategies targeting macrophage metabolism and redox balance, together with advances in macrophage-directed drug delivery systems, have emerged as promising approaches for modulating pulmonary inflammation and tissue injury. This review summarizes recent understanding of immunometabolic remodeling in pulmonary macrophages under homeostatic and pathological conditions and discusses emerging therapeutic perspectives targeting macrophage metabolism in chronic respiratory diseases.
Zhen Yuan, Ahmad Alhaskawi, Yejiang Tang et al.· Frontiers in Pharmacology· 0 citations
Radiation-induced lung injury (RILI) is a major dose-limiting toxicity of chest radiotherapy (RT), and its occurrence and development are closely related to the complex role of macrophages. RT significantly modulates the recruitment and functional status of macrophages. In the early stage, macrophages predominantly exhibit a pro-inflammatory M1 phenotype, releasing a large amount of inflammatory factors and exacerbating lung tissue damage. In the late stage, they shift to a pro-fibrotic M2 phenotype, promoting fibroblast activation, extracellular matrix accumulation, and epithelial-mesenchymal transition, thereby facilitating the progression of pulmonary fibrosis. In addition, the metabolic reprogramming induced by RT significantly affects the function of macrophages, manifested by imbalances in glucose, lipid, and amino acid metabolism and mitochondrial dysfunction, further reinforcing phenotypic polarization and functional heterogeneity. This complexity offers diversified strategies for the treatment of RILI by targeting macrophages, including phenotypic regulation, metabolic intervention, delivery systems and cell engineering development, and combination therapy, demonstrating new potential for mitigating RILI. However, the widespread use of immune checkpoint inhibitors has exacerbated the difficulty in preventing and treating RILI, necessitating urgent exploration of effective and safe intervention measures.
Xiaochi Ma, Jie Lu, Tao Zhong et al.· Frontiers in Immunology· 0 citations
Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive extracellular matrix deposition, tissue remodeling, and irreversible loss of lung function. Although inflammation contributes to disease progression, increasing evidence indicates that immunometabolic reprogramming is a central driver of fibrotic persistence. Alterations in glycolysis, mitochondrial function, lipid metabolism, and redox homeostasis actively regulate immune responses, fibroblast activation, and epithelial cell dysfunction, thereby sustaining a profibrotic microenvironment. This review synthesizes current advances in understanding how metabolic pathways regulate immune and structural cell behavior during pulmonary fibrosis. Particular emphasis is placed on metabolic checkpoints, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and nicotinamide adenine dinucleotide (NAD+)-dependent signaling, which integrate metabolic and inflammatory responses. We further discuss how mitochondrial dysfunction, hypoxia-inducible factor-1α (HIF-1α), reactive oxygen species (ROS), cellular senescence, and metabolic memory contribute to disease persistence. Emerging evidence supports metabolic crosstalk between immune cells and fibroblasts as a key mechanism driving fibrotic remodeling. Finally, we evaluate therapeutic strategies targeting immunometabolic pathways and discuss current translational challenges, including cellular heterogeneity, pathway redundancy, and limited clinical validation. Collectively, this review highlights immunometabolic regulation as a promising therapeutic framework and identifies opportunities for precision-based interventions in pulmonary fibrosis.
Hemraj Singh, Anushka Purwar, R. Taliyan· International Immunopharmaco...· 0 citations
Inflammation is a fundamental biological response required for host defense, tissue repair, and maintenance of homeostasis. Although acute inflammation is protective and self-limiting, persistent or dysregulated inflammation contributes to the initiation and progression of many chronic diseases. This review aims to examine the molecular mechanisms through which inflammation influences disease progression and to discuss major therapeutic targets and emerging anti-inflammatory strategies. Inflammatory responses are coordinated by immune and non-immune cells, including macrophages, neutrophils, lymphocytes, endothelial cells, epithelial cells, and stromal cells. These cells communicate through cytokines, chemokines, prostaglandins, reactive oxygen species, and damage-associated molecular patterns. Key signaling pathways, including NF-κB, JAK/STAT, MAPK, Toll-like receptor signaling, and inflammasome activation, regulate inflammatory gene expression, immune-cell recruitment, and tissue remodeling. When inflammation fails to resolve, sustained cytokine production, oxidative stress, immune dysregulation, fibrosis, angiogenesis, and extracellular matrix remodeling promote disease progression in cancer, autoimmune disorders, cardiovascular disease, metabolic dysfunction, neurodegeneration, and chronic infections. Therapeutic targeting of inflammatory pathways has advanced substantially through corticosteroids, non-steroidal anti-inflammatory drugs, biologics, cytokine blockade, JAK inhibitors, COX inhibitors, and emerging inflammasome inhibitors. Understanding the molecular basis of inflammation is essential for developing precise and effective therapies. Future strategies should focus on biomarker-guided treatment, resolution-based therapies, RNA-based approaches, microbiome modulation, and personalized interventions that suppress pathological inflammation while preserving protective immunity.
Unknown authors· Genetics and Molecular Resea...· 0 citations
Skin wound healing is a cascade of complex biological processes that ensure tissue repair, one of the key mechanisms being macrophage polarization, which regulates the transition from a pro‑inflammatory to an anti‑inflammatory state. Disruptions in this process lead to chronic inflammation, fibrosis, and delayed tissue recovery. Current research aimed at modifying the wound bed microenvironment through immunomodulation focuses on the use of cytokines and growth factors such as IL‑4, IL‑10, PDGF, VEGF, IGF‑1, FGF‑10, and others to modulate macrophage activity. All these biomolecules, when incorporated into nanomaterials and delivery systems, help accelerate healing, reduce scarring, and regulate inflammation. In oncology and inflammatory diseases, the possibility of switching macrophages between M1 and M2 phenotypes is also being studied to achieve therapeutic goals. The effectiveness of such approaches is enhanced by the use of modern carriers that ensure targeted delivery and controlled release of cytokines. This work reviews recent advances in the application of cytokines and growth factors incorporated into various systems to modulate macrophages and their phenotypes, as well as their use in developing personalized and effective treatments for various pathologies, particularly skin injuries.
N. V. Kolesnikova, G. P. Chuprynin, K. Melkonian· Вестник Пермского университе...· 0 citations
