The Emerging Role of Ly6G⁺Nur77⁺ Lung Macrophages in Type-2 Allergic Inflammation: A Comprehensive Review on Asthma...

Asthma remains a major health challenge affecting over 300 million people worldwide, with severe, steroid-resistant phenotypes affecting 5-10% of patients who fail to respond to current therapies. This review examines the emerging role of Ly6G⁺Nur77⁺ lung macrophages in allergic airway inflammation and asthma pathogenesis, and discusses their potential as novel therapeutic targets.

Advances in single-cell RNA sequencing and high-dimensional profiling have revealed an atypical lung macrophage population co-expressing the granulocyte marker Ly6G and the orphan nuclear receptor Nur77 (Nr4a1). Despite surface expression of Ly6G, these cells exhibit macrophage morphology (CD64⁺, F4/80⁺, MerTK⁺) and are distinct from neutrophils. They sense allergens via protease-activated receptor 2 (PAR2) and initiate early Type-2 immune responses by promoting dendritic cell migration through cysteinyl leukotriene production. In animal models, loss of Nur77 signaling exacerbates airway hyperresponsiveness, eosinophilic inflammation, and mucus hypersecretion, indicating a protective regulatory function. Conversely, chronic activation of these cells contributes to pathological airway remodeling via arginase-1-mediated collagen deposition and fibrosis. Human translational data link reduced Nur77 expression to asthma severity and steroid resistance. Ly6G⁺Nur77⁺ lung macrophages represent a functionally distinctmacrophage population with a dual role in asthma, acting as early sentinelsthat initiate allergen-driven Th2 responses while also exerting regulatorycontrol over inflammation resolution. Their involvement in both protectiveand pathological pathways positions them as promising targets for endotype-specific therapeutic strategies in severe and steroid-resistant asthma.