mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis.

Summary

Using human LAM lungs, organoids, precision-cut lung slices, and transgenic mice, the authors show that LAM cell–derived IL-6 induces endothelin-1 (Edn1) and nuclear sequestration of FoxO1 in alveolar type 2 cells, driving senescence and impaired epithelial repair. Rapamycin and IL-6 receptor blockade (tocilizumab) reduced AT2 senescence and improved repair, suggesting a combinatorial therapeutic strategy.

Key Findings

• Senescence markers (p21, p16, SenMayo) are increased in LAM lungs and colocalize with alveolar type 2 (AT2) cells.
• LAM models induce mTOR-dependent AT2 senescence in vitro and in vivo; LAM cell–derived IL-6 triggers AT2 p16/p21, impairs epithelial wound repair, and correlates with lung function.
• Rapamycin and tocilizumab reduce AT2 p21 accumulation; IL-6R blockade enhances epithelial repair, implicating an IL-6–Edn1–FoxO1 axis as a therapeutic target.

Clinical Implications

Supports testing combined IL-6 receptor blockade with mTOR inhibition to limit lung damage and preserve alveolar repair in LAM; provides biomarkers (p16/p21 in AT2) to monitor response.

Limitations

• Preclinical design; no randomized clinical outcomes in LAM patients
• Potential variability in human tissue sources and heterogeneity of LAM lesions

Future Directions

Phase 2 trials combining IL-6R blockade with mTOR inhibitors in LAM with embedded mechanistic biomarkers (AT2 p16/p21, Edn1/FoxO1 signaling) and lung repair endpoints.