Targeting the immune microenvironment in Duchenne muscular dystrophy: roles of macrophages, eosinophils, regulatory T cells, and neutrophils

Duchenne muscular dystrophy (DMD) is a progressive, life-limiting muscle disease caused by dystrophin deficiency and characterized by recurrent myofiber necrosis, persistent inflammation, and fibrosis. Although dystrophin-restoring and disease-modifying therapies are advancing, none fully arrests progression, and broad immunosuppression can also attenuate reparative responses. This review critically examines four immune-cell populations in dystrophic muscle: neutrophils, macrophages, eosinophils, and regulatory T cells (Tregs). Neutrophils contribute early oxidative and proteolytic injury through myeloperoxidase and elastase, whereas the role of neutrophil extracellular traps in DMD remains unproven. During normal regeneration, pro-inflammatory macrophages first clear debris and activate repair; they subsequently adopt pro-resolving states that support myogenesis. In DMD, continuous injury disrupts this sequence, sustaining mixed inflammatory and profibrotic macrophage programs, including arginase and TGF-β-associated remodeling. Eosinophil–fibro-adipogenic progenitor (FAP) signaling is context-dependent: experiments in acute injury and young mdx mice differ from findings in aged dystrophic models, and human evidence is limited. Muscle Tregs can restrain inflammation and support regeneration through macrophage reprogramming, amphiregulin, and the FAP–IL-33–ST2 axis. Recent single-cell and lineage studies further identify FAPs, resident macrophages, and trained innate immunity as interconnected therapeutic nodes. Selective, stage-specific modulation of pathogenic immune functions—while preserving host defense and regeneration—should therefore complement, rather than replace, dystrophin-directed treatment.