Innate immune circuits in acute lung injury: macrophage plasticity, ILC crosstalk, and tissue repair failure.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are traditionally understood as hyperinflammatory syndromes characterized by cytokine excess, neutrophil infiltration, and disruption of the alveolar-capillary barrier. However, this framework does not fully explain why some injured lungs undergo effective resolution whereas others progress toward persistent inflammation, defective epithelial regeneration, and long-term pulmonary dysfunction. Increasing evidence suggests that ALI is better conceptualized as a disorder of dysregulated tissue-centered innate immune circuits rather than a simple consequence of uncontrolled inflammation. Among the key cellular regulators of these circuits, macrophages and innate lymphoid cells (ILCs), especially ILC2s, play central and complementary roles. Macrophages function as early sentinels, inflammatory amplifiers, efferocytic cleaners, and reparative coordinators, with their impact determined by lineage origin, temporal state transitions, and niche-dependent plasticity. ILCs, in parallel, translate epithelial alarm signals into tissue-adaptive responses and contribute to barrier protection, homeostatic restoration, and modulation of macrophage function. Importantly, macrophages, ILCs, and epithelial cells form an interdependent communication network that governs the balance between inflammatory escalation and successful repair. When this network becomes disrupted, the injured lung shifts from coordinated recovery to failed repair. In this review, we discuss macrophage heterogeneity and plasticity in ALI, epithelial-macrophage and macrophage-ILC crosstalk, mechanisms of inflammatory resolution and repair failure, and emerging therapeutic opportunities aimed at restoring innate immune circuit competence in the injured lung.