Inhibition of LCP2 in T cells alleviated apoptosis and oxidative stress via PD-1/PD-L1 in diabetic retinopathy

To identify platelet-related biomarkers in diabetic retinopathy (DR) and clarify the role of lymphocyte cytosolic protein 2 (LCP2) and the PD-1/PD-L1 pathway in DR pathogenesis, we employed STZ-induced diabetic rats and a high-glucose (HG) T cell-RPE cell co-culture model. Platelet-related genes were screened from DR datasets (GSE102485, GSE60436) through bioinformatics analysis. Core genes were validated by qRT-PCR in STZ rat retinas and HG-treated human retinal endothelial cells (HRMECs). STZ-diabetic rats received intravitreal injections of PD-1/PD-L1 inhibitor JQ-1, LCP2-shRNA, or a combination. Retinal tissue was examined for histopathological changes, inflammation, oxidative stress, Apoptosis (TUNEL), T cell infiltration, and protein expression (WB). In HG-exposed co-cultures of rat T cells and retinal pigment epithelial cells (RPECs), with or without LCP2 knockdown, we assessed cell viability, T-cell differentiation, Apoptosis, inflammation, oxidative stress, and signaling pathways (WB/qPCR). Nine core platelet-related genes were identified (e.g., CDC42, Lck, LCP2), with LCP2 showing the most significant upregulation in STZ rats and HG-treated HRMECs. In STZ rats, increased LCP2 and PD-1/PD-L1 expression was associated with retinal injury, inflammation, oxidative stress, Apoptosis, and Th1-skewed T cell infiltration. Both JQ-1 and sh-LCP2 monotherapy significantly reduced these pathological changes, with the combination therapy yielding a stronger effect. In HG co-culture, LCP2 upregulation impaired RPEC viability, elevated Apoptosis, inflammation, and oxidative stress, and promoted Th1/Th2 differentiation. These effects were reversed by LCP2 knockdown. Mechanistically, LCP2 exerted its effects through the PD-1/PD-L1-MKK/JNK/c-Jun axis and the mitochondrial Apoptosis pathway (Bax/Bcl-2, Caspase-3). LCP2 functions as a key platelet-related biomarker in DR and contributes to retinal damage in diabetes by activating PD-1/PD-L1 signaling, inducing Th1 inflammation, oxidative stress, and mitochondrial Apoptosis in retinal cells. Targeting the LCP2-PD-1/PD-L1 axis may offer a potential treatment approach for DR.

Diabetic retinopathy; LCP2; PD-1/PD-L1; Retinal pigment epithelial cells; STZ rats; T cells.