Abstract
Purpose :
Autoimmune uveitis (AU) is a sight-threatening autoimmune disease, but its underlying pathological mechanisms required to develop more efficient therapy remain poorly understood. It has been shown that histone deacetylase (HDAC) is upregulated in central system autoimmune diseases and is associated with pathogenesis. Therefore, we aimed to investigate the role of HDAC in autoimmune uveitis and its potential pathogenic mechanisms.
Methods :
We isolated the peripheral blood mononuclear cells from AU patients and the age-matched healthy subjects, and performed scRNA-seq analysis. Besides, we established the experimental autoimmune uveitis (EAU) model using interphotoreceptor retinal binding protein 1-20 and treated it with HDAC inhibitor (HDACi) Belinostat (I.P. injection, 30mg/kg) or vector alone from day 2-14. On day 14, fundus photography and histopathologic examination were perforemed to calculate clinical and pathologic scores (0-4). Furthermore, we extracted immune cells of cervical draining lymph nodes and retinas from Blank, EAU, and HDACi-treated EAU mice, and used scRNA-seq, flow cytometry, siRNA interference and other technologies to explore and verify the role of HDAC and its related potential molecular mechanisms in the immune response of EAU.
Results :
We found elevated HDAC in the peripheral circulation of AU patients, and inhibiting HDAC effectively rescued the Th17/Treg imbalance and alleviated EAU (Fig 1). In addition, inhibiting HDAC reduced inflammatory gene expression and inflammatory response-related processes in myeloid cells and lymphocytes. Moreover, the proportion of Treg cells increased and exerted more anti-inflammatory and immunomodulatory effects. Importantly, HDAC exerted a positive regulatory effect on Th17 cells. In vivo and in vitro experiments, we found that HDACi effectively inhibited CDK6, a newly identified key pathogenic factor in Th17 cells, and suppressed its positive feedback with ID2 and downregulated PIM1, ultimately reducing the release of the pathogenic factors GM-CSF and IL-17 (Fig 2).
Conclusions :
Targeting inhibition of HDAC can significantly inhibit the activation of the CDK6/ID2/PIM1 pathway in Th17 cells to alleviate EAU. This finding suggests that HDAC may be a potential therapeutic target for AU and it broadens new insights into the pathogenesis of T-cell-mediated autoimmune diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.