Eosinophil peroxidase promotes the switch from pro-inflammatory to pro-resolving macrophages and ameliorates LPS-induced lung inflammation.

Eosinophils are traditionally recognized as immune effector cells in allergic and parasitic diseases, but their emerging roles in tissue homeostasis make them particularly intriguing cells to study in the context of tissue inflammation. Our study uncovers a previously unrecognized crosstalk between eosinophils and macrophages that is essential for resolving inflammation. Single-cell RNA sequencing shows that eosinophil deficiency leads to a global hyperactivated monocyte/macrophage lineage, underscoring the baseline regulatory role of eosinophils in myeloid homeostasis. We identify eosinophil peroxidase (EPX), a protein long associated with cytotoxicity and tissue damage, as the key mediator of macrophage regulation by eosinophils. We demonstrate that EPX orchestrates a time-dependent reprogramming of macrophages, driving a transition from a pro-inflammatory to a pro-resolving phenotype. This shift is characterized by metabolic flexibility, transient mitochondrial activation followed by redox homeostasis, and enhanced efferocytosis. This EPX-driven macrophage shift dependents on CD11b signaling. Notably, systemic or intranasal EPX administration attenuates LPS-induced acute lung injury, preserving alveolar macrophages and promoting a regulatory interstitial macrophage signature. Our findings reveal a previously unrecognized EPX-CD11b-metabolic axis that drives macrophage-mediated resolution of inflammation.