Alpha-1 antitrypsin–glucocorticoid receptor axis: a new pathway in immune modulation

Alpha-1 antitrypsin (AAT) has been reported to interact with the glucocorticoid receptor (GR) and modulate its signaling. We extended these findings by testing whether native (nAAT) and oxidized AAT (oxAAT) bind GR. Binding of native and modified AAT (oxidized and cleaved) to GR and candidate receptors (LRP1, SR-B1, TfR, CD36) was assessed by ELISA. AAT-GR colocalization was examined in PBMCs and macrophage models by confocal microscopy and co-immunoprecipitation. NR3C1 (GR) mRNA in PBMCs was analyzed after 24 h of treatment with AAT or dexamethasone. nAAT and oxAAT bound GR (EC₅₀ 0.9 and 2.6 µM) and LRP1 (EC₅₀ 2.9 and 1.3 µM), whereas binding to SR-B1, TfR, and CD36 was weak (EC₅₀ > 5 µM). Cleaved AAT showed no binding. AAT-GR colocalization was present in non-activated PBMCs but absent in macrophages, where GR was predominantly nuclear. Both nAAT and oxAAT significantly reduced NR3C1 mRNA, similar to dexamethasone. nAAT and oxAAT, but not cleaved forms of AAT, bind GR in vitro and associate with cytoplasmic GR in non-activated immune cells. Our results support the role of AAT in regulating GR signaling and highlight the AAT-GR axis as a putative mechanism of immune regulation.