Dual role of macrophage heterogeneity in allergic inflammation: from mechanism to targeted therapy

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.