Single-cell RNA sequencing indicates AP-1 as a potential therapeutic target for autoimmune uveitis

Abstract

Autoimmune uveitis (AU) is a sight-threatening eye disease, marked by a complex pathogenesis and limited treatment options. Herein, we conducted single-cell RNA sequencing (scRNA-seq) on the spleen and cervical draining lymph nodes (CDLNs) of both normal and experimental autoimmune uveitis (EAU) mice and found common alterations in celluar composition and transcriptional regulation occurred throughout the EAU process. Moreover, we identified activator protein-1 (AP-1) as a pivotal disease-related molecule in the pathogenesis of EAU. Inhibiting AP-1 alleviated symptoms of EAU and reduced the retina infiltration of T helper 17 cells (Th17) and Th1 cells. Additionally, following treatment with the AP-1 inhibitor, both the spleen and CDLNs showed decreased Th17 and Th1 cell proportions. Meanwhile, in vitro studies revealed that treatment with AP-1 inhibitor reduced the level of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-23 (IL-23), two pivotal molecules implicated in the Th17 cell pathogenicity, during EAU. The adoptive transfer experiment also showed that inhibiting AP-1 in CD4+ T cells suppressed their ability to elicit EAU. Altogether, our study demonstrates that AP-1 might involved in EAU pathogenesis by supporting Th17 cell pathogenicity via the GM-CSF/IL-23 feedback loop. Thus, AP-1 inhibition might be a novel treatment strategy for uveitis.

Keywords: AP-1; GM-CSF/IL-23; Single-cell RNA sequencing; Th17 cells; Uveitis.