Ifi27l2a Facilitates the Recruitment of Pathogenic T Cells by Retinal Microglia in the Initiation Phase of Experimental Autoimmune Uveoretinitis.

Abstract

The mechanisms by which pathogenic T cells enter the immune-privileged retina at the onset of uveitis remain unclear. To identify regulatory targets that promote retinal inflammation, we established an experimental autoimmune uveoretinitis (EAU) model by immunizing C57BL/6J mice with IRBP651-670 and dynamically evaluated retinal inflammation after induction; fundus lesions were prominent, with the first 14 days representing the initiation phase, Days 14-28 the amplification phase, Days 28-35 the peak phase, and Days 35-42 the regression phase. We characterized retinal cellular alterations from the pre-inflammatory stage to the peak stage using single-cell transcriptomic analysis, and found that retinal immune cells changed in parallel with EAU severity, while immune-cell interactions were strongest on Day 14, especially between microglia and T cells through multiple chemokine-related pathways. We then identified key cell populations and candidate targets through integrated analyses and functional validation, and Ifi27l2a emerged as a core gene associated with inflammatory and immune responses in retinal microglia on Day 14. In vitro knockdown of Ifi27l2a in LPS-activated BV-2 cells reduced inflammatory mediator production and abolished Th1/Th17 induction. In vivo targeting of Ifi27l2a attenuated EAU severity and restored the balance of T-cell subsets. These findings indicate that microglia are highly activated before retinal inflammation becomes prominent and that Ifi27l2a regulates this early pathogenic process.