Essential roles of mechanistic target of rapamycin in the induction of steroid resistance in group 2 innate lymphoid cells and severe asthma

Approximately 5% to 10% of asthma patients are resistant to glucocorticoid therapy; however, the mechanisms by which this resistance develops remain unclear. The present study investigated whether and how mechanistic target of rapamycin (mTOR) is involved in the development of steroid resistance using in vitro and in vivo murine models. The interleukin (IL)-33/thymic stromal lymphopoietin (TSLP)/IL-7-induced growth of group 2 innate lymphoid cells (ILC2) in vitro was resistant to dexamethasone (DEX), but suppressed by everolimus, an mTOR Inhibitor, in a concentration-dependent manner. The inhibition of ILC2 growth by the combination of DEX and everolimus was significantly stronger than that by everolimus monotherapy. The combination of the pan-class I phosphatidylinositide-3 kinase inhibitor, buparlisib and the pan-Akt inhibitor, capivasertib also attenuated the resistance of IL-33/TSLP/IL-7-exposed ILC2s to DEX. The expression of the antiapoptotic factor, B-cell lymphoma-extra large, induced by IL-33/TSLP/IL-7 in ILC2s was significantly reduced by everolimus. Additionally, everolimus effectively suppressed the IL-33/TSLP/IL-7-induced phosphorylation of glucocorticoid receptors (GR) at the Ser234 residue, which has been reported to cause GR dysfunction. In the steroid-resistant asthma mouse model in vivo, under treatment with everolimus, DEX inhibited the development of airway remodeling and increased the number of ILC2s in the lungs. The present results suggest that the phosphoinositide 3-kinase/protein kinase B/mTOR pathway plays an essential role in the development of steroid resistance in ILC2s and asthma pathogenesis through both the expression of B-cell lymphoma-extra large and phosphorylation of GR. Therefore, mTOR inhibitors have the potential to restore glucocorticoid sensitivity and, thus, exert steroid-sparing effects in severe asthma patients. SIGNIFICANCE STATEMENT: Approximately 5% to 10% of asthma patients exhibit resistance to steroid therapy, posing a major clinical challenge due to limited treatment options. This study demonstrates that activation of the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (mTOR) pathway induces steroid resistance in group 2 innate lymphoid cells. Targeting mTOR with everolimus restores steroid sensitivity, highlighting mTOR inhibition as a promising pharmacotherapy for steroid-resistant asthma.

Asthma; Glucocorticoid receptor; Group 2 innate lymphoid cells; Mechanistic target of rapamycin; Steroid resistance.