Jul 2026· International Immunopharmacology· Vol 186, pp.
117112
· 0 citations· 137 references
Medicine
TL;DR
This review systematically synthesizes the molecular mechanisms governing macrophage autophagy and its dual role in allergic diseases, and summarizes potential therapeutic strategies targeting macrophage autophagy, such as budesonide/simvastatin combination therapy and rapamycin derivatives, along with their clinical translation prospects.
Abstract
Macrophages are pivotal effector cells within the innate immune system, playing a central role in inflammation regulation, tissue homeostasis, and immune defense. Recent studies have demonstrated that macrophage autophagy-a highly conserved process essential for cellular homeostasis-plays a critical role in dynamically balancing immune responses by selectively eliminating damaged organelles, pathogens, and protein aggregates. Macrophage autophagy is finely regulated by various signaling pathways, such as mTOR and NF-κB, and its dysfunction is closely associated with the onset and progression of allergic diseases. This review systematically synthesizes the molecular mechanisms governing macrophage autophagy and its dual role in allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. It highlights the functions of key signaling pathways (e.g., mTOR, NF-κB) and regulatory factors (e.g., p62, Beclin-1, LC3) and explores the crosstalk between macrophage autophagy, immunometabolism, and cellular polarization. Explores the crosstalk between macrophage autophagy, immunometabolism, and cellular polarization, and further elaborates the reciprocal regulatory network of autophagy and metabolic reprogramming within allergic inflammatory microenvironment. Furthermore, the review summarizes potential therapeutic strategies targeting macrophage autophagy, such as budesonide/simvastatin combination therapy and rapamycin derivatives, along with their clinical translation prospects, with the aim of providing a theoretical foundation for developing novel, autophagy-targeted precision therapies for allergic diseases.
Allergic inflammation, such as allergic asthma, allergic rhinitis, and atopic dermatitis, shares many pathogenic hallmarks, including inappropriate activation of type 2 immune responses, tissue barrier dysfunction, and disruption of local homeostasis. Due to their remarkable plasticity and tissue adaptability, macrophages are crucial effector cells of the innate immune system that play complex, context-dependent dual roles in allergic inflammation. On the one hand, macrophages are implicated in the persistence of chronic inflammation, thereby boosting Th2 cell recruitment, eosinophil infiltration, antigen processing, chemokine secretion, inflammatory mediator release, and tissue remodeling. On the other hand, they promote the resolution of inflammation by triggering barrier repair, producing anti-inflammatory mediators including TGF-β and IL-10, and phagocytosing apoptotic cells. Recent single-cell transcriptomic and functional studies have demonstrated that macrophages are dynamically distributed along an activation continuum rather than merely fitting into the traditional M1/M2 polarization. Functional states are determined by cellular origin, illness stage, tissue niche, and complex regulatory networks. For macrophages implicated in airway inflammation and remodeling, non-IgE-dependent nasal neurogenic reflexes, skin barrier disruption, itch neuroimmune circuits, and inflammation resolution, distinct barrier tissues-such as the lung, nasal mucosa, and skin-show notable tissue specificity. The pathogenic and preventive functions of macrophages in allergic inflammation are systematically summarized in this review, which also emphasizes a continuous spectrum of macrophage activation and incorporates interactions among metabolic reprogramming, pyroptosis, epigenetic control, and trained immunity. Given the dynamic and microenvironment-dependent nature of macrophage function, future treatment approaches need to shift from broad anti-inflammatory therapies to precision reprogramming that is stage-specific and tissue-tuned. During the start and amplification stages of inflammation, therapeutic strategies should target pathogenic M2a-like programs, chemokine networks, monocyte recruitment, and excessive pyroptotic responses. On the other hand, M2b/M2c and pro-resolving macrophage-mediated efferocytosis, immunological tolerance, and tissue healing should be the focus of tactics in the resolution and repair stages. Furthermore, the management of allergic diseases may shift from empirical anti-inflammatory therapy to mechanism-guided precision interventions through patient stratification based on single-cell omics, spatial omics, and macrophage-associated biomarkers.
Guijie Yuan, Meng Wang, Zhiwei Cao et al.· International Immunopharmaco...· 1 citation
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.
Karthika Padmavathy, M. Beevi, Ajab Singh Choudhary et al.· Genetics and Molecular Resea...· 0 citations
As central mediators bridging innate and adaptive immunity, macrophages exhibit functional plasticity that is precisely governed by dynamic epigenetic networks, The histone H3K27 demethylase KDM6B acts as a key epigenetic hub that mediates the epigenetic remodeling of macrophages in response to environmental signals and exerts pleiotropic regulatory roles across diverse pathophysiological contexts. In the tumor microenvironment, KDM6B drives the polarization of tumor-associated macrophages toward an M2-like immunosuppressive phenotype, reshapes cellular metabolism, and consequently promotes tumor immune escape and progression. Similarly, in inflammatory and autoimmune diseases, KDM6B acts as a core epigenetic regulator of the NF-κB pathway, initiating and sustaining chronic inflammation by modulating inflammasome activity and accelerating cytokine release. In fibrotic diseases, KDM6B facilitates macrophage M2 polarization and their transdifferentiation into myofibroblasts, positioning itself as a central driver of organ fibrosis initiation and progression. In infectious diseases, KDM6B plays a dual role: it enhances antiviral immune responses to strengthen host defense, yet can also be hijacked by pathogens such as Leishmania donovani and mycobacteria, which induce an immunosuppressive phenotype in macrophages that facilitates pathogen survival. Beyond these contexts, KDM6B also regulates the function of tissue-resident macrophage subsets including microglia, thereby participating in pathophysiological processes such as neuroinflammation and maternal-fetal tolerance. Collectively, KDM6B-mediated regulation of macrophages is highly dependent on the microenvironment, conferring both promising therapeutic potential and practical challenges. Further elucidation of its precise regulatory circuits in distinct pathological microenvironments will be essential for the development of targeted therapeutic strategies.
Hai-Yan Wang, Xue-Dong Fan, R. Lin et al.· Biomedicine & pharmacotherap...· 0 citations
Chronic upper and lower airway inflammatory diseases (such as allergic rhinitis, chronic rhinosinusitis, and bronchial asthma) are a group of highly heterogeneous disorders primarily characterized by immune imbalance and persistent inflammation as their core features, which seriously affect patients’ quality of life. As an important component of the immune system, macrophages can undergo functional polarization in response to distinct inflammatory microenvironments, exerting divergent pro-inflammatory or anti-inflammatory effects. They also form intricate interaction networks with other immune cells to jointly regulate the progression of chronic airway inflammation. Although the regulation of macrophage plasticity is regulated by multiple aspects, metabolic reprogramming has emerged as a pivotal mechanism modulating macrophage polarization and function. This review systematically summarizes the interplay between macrophage polarization and other immune cells, focusing on the impact of distinct phenotypes and their regulatory pathways on chronic airway inflammatory diseases. Furthermore, we discuss the therapeutic potential of targeting metabolic reprogramming, providing new insights for the precise treatment of chronic upper and lower airway inflammatory diseases.
Unknown authors· Frontiers in Immunology· 0 citations
Regulatory T cells (Tregs) are essential for maintaining immune tolerance. We recently identified chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, as a critical regulator of Treg function. Treg activation induces CMA, but this response is markedly diminished with aging. Mice lacking CMA specifically in Tregs develop systemic inflammation, impaired immune tolerance and reduced lifespan. We confirm that CMA is a fundamental mechanism supporting Treg suppressive function as CMA-deficient Tregs are unable to suppress intestinal inflammation in a model of inflammatory bowel disease and fail to block the anti-oncogenic immune response activated in a syngeneic tumor model. Mechanistically, CMA supports metabolic fitness, remodels immune-related protein networks, and promotes degradation of the m6A RNA demethylase FTO, linking lysosomal proteostasis to epitranscriptomic control of IL-2 responsiveness. Restoration of CMA in aged mice improves Treg function, highlighting CMA as a promising therapeutic target for both inflammatory diseases and cancer immunotherapy.
Asthma is a complex inflammatory disease where oxidative stress and immune metabolic dysfunction coexist. As master regulators of this interface, macroautophagy/autophagy and nitric oxide (NO) signaling govern immune polarization, metabolic flux, and mitochondrial integrity. While NO functions as a redox messenger that affects both protective and pathogenic outcomes, autophagy maintains cellular homeostasis through coordinated degradation and recycling processes. These pathways come together to form a regulatory triad that controls T-cell differentiation, macrophage activation, and airway remodeling. Here, we outline the ways in which autophagy-NO interactions alter immune metabolism to fuel inflammation in asthma and investigate their potential as a combined therapeutic target. We offer a systems-level perspective of immune reprogramming by mapping important molecular nodes, including those involving MTOR, AMPK, BECN1, NOS2/iNOS, and NOS3/eNOS, and connecting them to metabolic checkpoints. Finally, as a potential avenue that can offer improved efficacy and durability in the management of asthma, we highlight translational strategies that combine autophagy modulators, NO donors or inhibitors, and metabolic regulators.Abbreviations: ASM: airway smooth muscle; COPD: chronic obstructive pulmonary disease; DC: dendritic cell; FAO: fatty acid oxidation; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; L-NIL: L-N6-(1-Iminoethyl)lysine (selective NOS2 inhibitor); M1 and M2: macrophage pro-inflammatory and anti-inflammatory polarization states; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2; NOS3/eNOS: nitric oxide synthase 3; OXPHOS: oxidative phosphorylation; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; ROS: reactive oxygen species; TGFB1/TGF-β1: transforming growth factor beta 1; Treg: regulatory T cell; TSLP: thymic stromal lymphopoietin.
Sohrab Khan, A. Sammad, Philippe Madjirebaye et al.· Autophagy· 0 citations
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