Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell functionFan, Nai-Wen (Avtor) Yu, Man (Avtor) Wang, Shudan (Avtor) Blanco, Tomas (Avtor) Lužnik Marzidovšek, Zala (Avtor) Chauhan, Sunil K. (Avtor) Viswanath, Veena (Avtor) Gil, Daniel (Avtor) Held, Katherine S (Avtor) Chen, Yihe (Avtor) Reza, Dana (Avtor) dry eye diseasetreatmentT cellsTh17 immunityautoimmunityThere is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II+CD11b+cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED- derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.Rag1-/- mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.20242026-01-13 15:15:44Neznano25206UDK: 617.7ISSN pri članku: 1933-0219DOI: 10.1016/j.mucimm.2024.11.002COBISS_ID: 220814595sl