Effect of Endogenous FGF21 Deficiency on the Inflammatory Microenvironment of the Retina.

BACKGROUND

While the systemic metabolic role of fibroblast growth factor 21 (FGF21) is well-established, its function in retinal homeostasis and its link to retinal diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) remains poorly understood. This study investigated the impact of endogenous FGF21 deficiency on the retinal immune microenvironment.

METHODS

Retinal structure was assessed in FGF21 KO and wild-type mice using spectral-domain optical coherence tomography. Transcriptomic profiles of the retina/choroid were analyzed by RNA-seq. Differentially expressed genes (DEGs) were identified (DESeq2, FDR <0.05), clustered, and interrogated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Immune-cell composition was inferred with ImmuCellAI.

RESULTS

FGF21 KO mice showed no overt retinal structural defects under baseline conditions. Nevertheless, 449 DEGs were identified (293 up, 156 down in knockout). Pathway analysis revealed significant enrichment of cytokine-cytokine receptor interaction, chemokine signaling, and Jak-STAT cascades. Immune deconvolution indicated a significant increase in M2-polarised macrophages (p < 0.01) without change in total macrophage number. Expression of key inflammatory mediators including Il1b was concordantly altered.

CONCLUSIONS

This work establishes endogenous FGF21 as a crucial local immunomodulator and defines a novel mechanistic link to retinal disease susceptibility, supporting its further exploration as a therapeutic target.