Age-related alterations in retinal structure and blood perfusion in TIPE2 gene-knockout mice

Tumor necrosis factor-α-induced protein 8-like 2 (TNFAIP8L2/TIPE2) is a critical regulator of immune and inflammatory responses. Although its roles in diabetic retinopathy and choroidal neovascularization have been reported, its influence on the natural state of retina remains unclear. This study investigated whether TIPE2 knockout alone affects retinal structure and function. Wild-type (WT) and TIPE2^-/- mice were categorized into juvenile, adult, and late middle-aged groups. Retinal lamellar thickness and blood perfusion across 17 regions were quantified using ultra-widefield swept-source optical coherence tomography and angiography (SS-OCT/OCTA). Generalized estimating equations (GEE) were applied to account for within-eye correlations and to test main effects of genotype and age. Genotype showed a significant main effect on superficial vascular plexus (Svp) perfusion, indicating overall lower Svp perfusion in TIPE2^-/- mice, whereas no significant main effects were detected for deep vascular plexus (Dvp) perfusion. TIPE2^-/- mice also exhibited reduced total retinal thickness, with the strong genotype-associated thinning observed in the inner nuclear layer (INL), inner plexiform layer (IPL), outer plexiform layer (OPL) and outer nuclear layer (ONL). Age exerted smaller effects, showing a significant main effect on total retinal thickness and retinal pigment epithelium (RPE) thickness. Pan-lactylation levels in retinal tissue were assessed by Western Blot and markedly upregulated in adult TIPE2^-/- retinas. These findings demonstrate that TIPE2 deficiency was associated with retina hypoperfusion and age-related retinal thinning, suggesting that TIPE2 plays an essential role in preserving the natural state of retina.