Itaconate Ameliorates Experimental Autoimmune Uveitis by Modulating Teff/Treg Cell Imbalance Via the DNAJA1/CDC45 Axis.

Abstract

Purpose: The aim of this study was to elucidate the effect of itaconate (ITA) on experimental autoimmune uveitis (EAU), to explore its potential mechanism, and to identify potential therapeutic targets.

Methods: We established an animal model of EAU by constructing an immune map of mice treated with ITA and exploring the therapeutic mechanism of ITA by single-cell RNA sequencing and flow cytometry.

Results: ITA mitigated ocular inflammation associated with EAU and reversed the pathogenic differentiation linked to Th17 induction by EAU, along with the reactive oxygen species (ROS) and oxidative stress pathways. Subsequent to ITA intervention, the downregulated differentially expressed genes in the T-cell subset primarily centered around the heat shock protein (HSP) family. Activation of HSPs reversed the anti-inflammatory effects of ITA in EAU mice. ITA decreased ROS levels and HSP expression in CD4+ T cells, with DnaJ heat shock protein family (HSP40) member A1 (DNAJA1) exhibiting the most notable alterations among the HSPs. ITA suppressed the expression of DNAJA1/cell division cycle protein 45 (CDC45), thereby disrupting the pathogenic division cycle of CD4+ T cells and reducing their proliferation. Inhibiting DNAJA1 also held promise for modulating the Th17/Treg imbalance. Notably, ITA curtailed the expansion of CD4+ T cells in uveitis patients.

Conclusions: Our research delved into the potential therapeutic mechanisms underlying ITA therapy in EAU, offering fresh perspectives on its utility in the treatment of autoimmune conditions. DNAJA1 emerges as a promising candidate for targeted therapeutic interventions in uveitis.