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Updated: Aug 29, 2026
Experimental Autoimmune Uveitis: An Intraocular Inflammatory Mouse Model
Published on: January 12, 2022
MC4R modulates autophagy and pyroptosis regulated by UCP1 in experimental autoimmune uveitis
ChunYing Jiang1, HongYu Zhao2, XiangHong An3
1Department of Ophthalmology, The First Hospital of Jilin University, Changchun City, Jilin Province, 130000, China.
Objective:
To explore melanocortin-4 receptor (MC4R) and uncoupling protein 1 (UCP1) expression and function in autoimmune uveitis (AU) and their regulation of retinal pigment epithelium (RPE) autophagy/pyroptosis, for therapies.
Methods:
EAU was induced in female C57BL/6 J mice; eyeballs underwent transcriptome sequencing. Bioinformatics and protein-protein interaction (PPI) network screened differentially expressed genes (DEGs) and core targets. Retinal damage was assessed by hematoxylin and eosin (H&E); cytokines and autophagy/pyroptosis markers by enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunofluorescence. In vitro, ARPE-19 cells were lipopolysaccharide (LPS)-stimulated to establish an inflammatory model; cell death/autophagy were evaluated by flow cytometry and monodansylcadaverine (MDC). RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), actinomycin D assays verified the interaction between MC4R and UCP1 and their effect on mRNA stability; small interfering RNA (siRNA) rescue experiments in vivo, in vitro confirmed that UCP1 mediates AU pathology via MC4R.
Results:
A total of 161 DEGs were identified, with MC4R and UCP1 hub genes aberrantly expressed in EAU tissues and LPS-treated cells. MC4R knockdown reduced clinical scores and inflammatory cell infiltration, and inhibited RPE autophagy/pyroptosis. UCP1 did not directly bind MC4R but indirectly regulated MC4R mRNA stability, downregulating MC4R protein expression. UCP1 knockdown exacerbated pathological retinal damage and RPE autophagy/pyroptosis, reversed by MC4R knockdown.
Conclusion:
Systemic MC4R modulation attenuates retinal inflammatory and histopathological damage in AU, associated with RPE autophagy-pyroptosis activation. UCP1 downregulates MC4R via indirect post-transcriptional regulation of mRNA stability, reversing these processes, offering new insights into the immunometabolic regulatory mechanisms underlying ocular autoimmune diseases.
