β-Catenin stabilization protects against alveolar hemorrhage through amphiregulin- and BATF-mediated Tregs.

Abstract

Alveolar hemorrhage (AH) is a life-threatening condition with high mortality, yet the immunological mechanisms governing disease severity remain poorly defined. Here, we demonstrate a protective role for T cell-intrinsic β-catenin stabilization in AH using a transgenic mouse model (CAT-Tg) in which β-catenin is stabilized under the Lck promoter. We found β-catenin stabilization induced a distinct T cell phenotype marked by expansion of central effector memory cells (CD44+CD122+Eomes+T-bet+) and suppression of proinflammatory signaling, including reduced phosphorylation of STAT1, STAT3, and JAK1. Pristane-induced AH was attenuated in CAT-Tg mice, which exhibited reduced lung injury, decreased proteinuria, and diminished pulmonary proinflammatory cytokine production compared with WT controls. Protection was associated with a marked expansion of FOXP3+ Tregs. Mechanistically, β-catenin stabilization enhanced lung expression of amphiregulin and BATF, mediators of Treg stability and tissue repair. Adoptive transfer of CAT-Tg-derived Tregs into WT mice conferred superior protection against AH, reducing lung inflammation and proteinuria. Transcriptomic analyses revealed enrichment of tissue repair and immune homeostasis pathways, including PI3K-Akt, angiogenesis, and STAT5 signaling. Collectively, these findings identify β-catenin as a regulator of a protective amphiregulin/BATF/Treg axis, highlighting an immunomodulatory pathway with therapeutic potential for AH and inflammatory lung disease.