β-Catenin Stabilization Protects Against Alveolar Hemorrhage Through Amphiregulin and BATF-Mediated Regulatory T Cells 2300906

Abstract

Abstract Introduction Alveolar hemorrhage (AH) is a life-threatening condition with a high mortality rate, yet the role of immune cells in its pathogenesis remains poorly defined. Here, we report the protective function of β-catenin stabilization under Lck promoter and its impact on AH. AH was induced using pristane, and CAT-Tg mice were significantly protected from lung damage, showing reduced proteinuria and decreased pulmonary proinflammatory cytokine production compared with wild-type (WT). This protection correlated with a marked increase in FOXP3+ regulatory T cells (Tregs) in CAT-Tg mice. We further identified a novel mechanism in which β-catenin stabilization enhances lung expression of Amphiregulin and BATF, two molecules essential for Treg function and tissue repair. Adoptive transfer of Tregs from CAT-Tg mice into WT mice with pristane-induced AH conferred superior protection, as evidenced by reduced lung inflammation and proteinuria. The systemic administration of a β-catenin agonist to mice with AH significantly attenuated disease severity. Our bioinformatic analysis confirmed that β-catenin stabilization upregulates pathways associated with tissue repair and immune homeostasis, including PI3K-Akt, angiogenesis, and STAT5 signaling. Methods Using transgenic mice with β-catenin stabilization (CAT-Tg), we demonstrate that CAT-Tg CD8+ T cells display increased central and effector memory subsets, elevated expression of CD44, CD122, Eomes, and T-bet, and reduced phosphorylation of STAT1, STAT3, and JAK1. Results These findings reveal that β-catenin stabilization protects against Alveolar hemorrhage by inducing a specialized T-cell phenotype and establishing a protective Amphiregulin—BATF—Treg axis. Conclusion This work not only uncovers a novel immunoregulatory pathway but also highlights β-catenin as a potential therapeutic target for AH and other cytokine storm mediated lung diseases Funding Source N/A Topic Categories Basic Autoimmunity (BA)