Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function

Nai-Wen Fan; Man Yu; Shudan Wang; Tomas Blanco; Zala Luznik; Sunil K Chauhan; Veena Viswanath; Daniel Gil; Katherine Held; Yihe Chen; Reza Dana

doi:10.1016/j.mucimm.2024.11.002

Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function

Mucosal Immunol. 2024 Nov 8:S1933-0219(24)00110-7. doi: 10.1016/j.mucimm.2024.11.002. Online ahead of print.

Authors

Nai-Wen Fan¹, Man Yu², Shudan Wang³, Tomas Blanco³, Zala Luznik³, Sunil K Chauhan³, Veena Viswanath⁴, Daniel Gil⁵, Katherine Held⁶, Yihe Chen⁷, Reza Dana⁸

Affiliations

¹ Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA; Department of Ophthalmology, Taipei Veterans General Hospital, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
² Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA; Department of Ophthalmology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, PR China.
³ Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA.
⁴ (Former) Development Sciences, AbbVie Inc., Irvine, CA 92612, USA.
⁵ (Former) Biological Research, Allergan plc, Irvine, CA 92612, USA.
⁶ Ophthalmology Discovery Research, AbbVie Inc., Irvine, CA 92612, USA.
⁷ Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA. Electronic address: yihe_chen@meei.harvard.edu.
⁸ Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA. Electronic address: reza_dana@meei.harvard.edu.

PMID: 39522611
DOI: 10.1016/j.mucimm.2024.11.002

Abstract

There 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.