ROS-NLRP3 Axis in Intestinal Epithelial Cells is Involved in the Development of Autoimmune Uveitis

Area of Science:

• Ophthalmology
• Immunology
• Gastroenterology

Background:

• Uveitis is a severe, blinding eye condition with poorly understood mechanisms.
• An imbalance between regulatory T (Treg) cells and T helper 17 (Th17) cells, influenced by genetics and environment, is central to uveitis development.
• The role of intestinal immune dysregulation in uveitis pathogenesis requires further investigation.

Purpose of the Study:

• To investigate the hypothesis that intestinal immune imbalance exacerbates experimental autoimmune uveitis (EAU).
• To elucidate the specific molecular pathways involved in intestinal inflammation during EAU.

Main Methods:

• Established an experimental autoimmune uveitis (EAU) mouse model using IRBP1-20 immunization.
• Analyzed immune cell populations (CD4+ T cells, dendritic cells, Treg/Th17 cells) in the intestinal lamina propria and lymph nodes via flow cytometry.
• Assessed intestinal barrier function using FITC-dextran permeability and RT-PCR for tight junction proteins (occludin, ZO-1).
• Quantified reactive oxygen species (ROS) and NLRP3 inflammasome components (NLRP3, caspase-1, IL-1β) in intestinal epithelial cells using ROS probes and Western blotting.
• Evaluated the therapeutic potential of antioxidant treatment on EAU progression and intestinal inflammation.

Main Results:

• Early EAU stages showed increased CD4+ T cells, dendritic cells, and memory CD4+ T cells in the intestinal lamina propria.
• Intestinal epithelial barrier dysfunction was evident, with increased permeability and reduced occludin/ZO-1 expression.
• Elevated ROS, NLRP3 inflammasome activation (NLRP3, caspase-1, IL-1β) were detected in the intestinal epithelium of EAU mice.
• Antioxidant administration ameliorated EAU severity and suppressed intestinal ROS-NLRP3 pathway activation.

Conclusions:

• The intestinal ROS-NLRP3 signaling axis plays a critical role in driving uveitis pathogenesis.
• Disruption of the intestinal barrier and subsequent immune cell infiltration contribute to EAU.
• Targeting the intestinal ROS-NLRP3 pathway offers a potential therapeutic strategy for uveitis.