Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis

BackgroundAutoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical hormone for reproduction, on the treatment of AU and the regulatory mechanisms remain unclear.MethodsTo this end, we established experimental autoimmune uveitis (EAU) animal models and constructed a high-dimensional immune atlas of EAU-model mice undergoing PRG treatment to explore the underlying therapeutic mechanisms of PRG using single-cell RNA sequencing.ResultsWe found that PRG ameliorated retinal lesions and inflammatory infiltration in EAU-model mice. Further single-cell analysis indicated that PRG reversed the EAU-induced expression of inflammatory genes (AP-1 family, S100a family, and Cxcr4) and pathological processes related to inflammatory cell migration, activation, and differentiation. Notably, PRG was found to regulate the Th17/Treg imbalance by increasing the reduced regulatory functional mediators of Tregs and diminishing the overactivation of pathological Th17 cells. Moreover, the Id2/Pim1 axis, IL-23/Th17/GM-CSF signaling, and enhanced Th17 pathogenicity during EAU were reversed by PRG treatment, resulting in the alleviation of EAU inflammation and treatment of AD.ConclusionsOur study provides a comprehensive single-cell map of the immunomodulatory effects of PRG therapy on EAU and elaborates on the possible therapeutic mechanisms, providing novel insights into its application for treating autoimmune diseases.

Automated summary

Autoimmune uveitis (AU) is a common autoimmune disease with a complex etiology and high morbidity. The effects and regulatory mechanisms of progesterone (PRG) on the treatment of AU are unclear. In this study, we found that PRG ameliorated retinal lesions and inflammatory infiltration in AU animal models by regulating inflammatory gene expression and Th17/Treg imbalance. PRG also reversed the pathological signaling pathways involved in AU inflammation. These findings indicate that PRG has the potential to be used as a treatment for AU and other autoimmune diseases.