Integrated Single-Cell Profiling Reveals TL1A as a Biomarker and Driver of Type 2 Inflammation via Macrophage-Dependent Immunoregulation in Asthma

Background: Asthma remains a global health burden, with its heterogeneity necessitating precision biomarkers and targeted therapies. Tumor necrosis factor-like ligand 1A (TL1A), a novel alarmin in the airway, remains poorly characterized in asthma pathogenesis. Methods: TL1A levels were measured in the sputum and serum samples of patients with various asthma phenotypes. Single-cell RNA sequencing of murine asthmatic lung and myeloid-cell-specific Tnfsf15 -knockout mice ( Tnfsf15 Mac-KO ) was performed, and the effects of anti-TL1A interventions were evaluated in allergen-induced asthma models. Results: TL1A levels were significantly elevated in the serum and sputum of patients with asthma and correlated with clinical disease severity, declining lung function, and blood eosinophil counts. Single-cell RNA sequencing identified macrophages as the primary immune cells expressing TL1A in the context of allergic lung inflammation. In the Tnfsf15 Mac-KO mice, allergen-induced airway inflammation, T helper 2 cytokine secretion, and mucus hypersecretion were attenuated. Mechanistically, TL1A induced C-C motif chemokine ligand 8 (CCL8) expression via the activation of death receptor 3, thereby driving type 2 inflammation. Critically, the anti-TL1A antibody interventions suppressed T helper 2-mediated responses and reduced the number of pathogenic CD8 + T cells in a dose-dependent manner. Conclusion: TL1A serves a dual role as a biomarker and therapeutic target in asthma, as it modulates macrophage-driven pathogenesis. TL1A inhibition disrupts CCL8/C-C motif chemokine receptor 8 signaling and pathogenic T-cell responses, providing a precision medicine strategy for asthma.