β-Catenin stabilization protects against alveolar hemorrhage through amphiregulin- and BATF-mediated Tregs
Fiona Mason, Hui Xiong, Ali Mobeen, Md Saddam Hossain, Sara Mahmudlu, Rosanne Trevail, Mikyal Mobeen, Li Chen, Sunny Lee, Tuncay Delibasi, Jyoti Misra Sen, Mobin Karimi
Fiona Mason, Hui Xiong, Ali Mobeen, Md Saddam Hossain, Sara Mahmudlu, Rosanne Trevail, Mikyal Mobeen, Li Chen, Sunny Lee, Tuncay Delibasi, Jyoti Misra Sen, Mobin Karimi
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Research Article Immunology

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.

Authors

Fiona Mason, Hui Xiong, Ali Mobeen, Md Saddam Hossain, Sara Mahmudlu, Rosanne Trevail, Mikyal Mobeen, Li Chen, Sunny Lee, Tuncay Delibasi, Jyoti Misra Sen, Mobin Karimi

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Figure 7

β-Catenin agonist treatment phenocopies genetic β-catenin stabilization and protects against pristane-induced alveolar hemorrhage.

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β-Catenin agonist treatment phenocopies genetic β-catenin stabilization ...
(A) Experimental schematic. WT mice were injected with pristane to induce alveolar hemorrhage (AH) and assigned to treatment groups as indicated. (B) Chemical structure of the β-catenin agonist. (C and D) Representative flow plots and quantification of lung Tregs (CD4+CD25+FOXP3+) in WT mice treated with vehicle or β-catenin agonist; lungs were harvested on day 14. (E and F) Gross and histological comparison of untreated WT controls and pristane-only WT mice (no vehicle or agonist). (G and H) Representative H&E-stained lung sections and corresponding pathology scores for cohorts in E and F. (I and J) Gross and histological comparison of pristane-injected WT mice treated with vehicle versus β-catenin agonist (10 μg per 20 g body weight). (K–M) Representative H&E-stained lung sections and quantitative pathology scoring for cohorts in I and J. Data are presented as mean ± SEM; sample sizes (n = 15–25 mice per group) are indicated in panels. Each experiment was repeated 3 times. Statistical significance was determined using the appropriate test; **P < 0.01, ***P < 0.001, ****P < 0.0001. Scale bar:50 μm.