SOCS3 regulates retinal angiogenesis through modulating microglia SPP1 expression

Abstract

Purpose : Pathological ocular angiogenesis has long been associated with microglia activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain largely elusive.

Methods : The floxed mice of the suppressor of cytokine signaling 3 (Socs3) (Socs3^f/f) were crossed with LysM Cre mice (Cre^LysM) to generate myeloid Socs3 knockout mice (Socs3^cKO). Socs3 overexpression flox/flox mice were crossed with Cre^LysM to generate myeloid Socs3 overexpression mice (Socs3^cOE). Spp1 knockout (Spp1^KO) mice were crossed with Socs3 cKO mice to generate Socs3^cKO;Spp1^KO double knockout mice (DKO). The mouse model of oxygen-induced retinopathy (OIR) and the laser-induced choroidal neovascularization (CNV) were used to mimic pathological proliferative retinal or choroidal angiogenesis aspects of retinopathy of prematurity and age-related macular degeneration, respectively. Single-cell RNA sequencing was conducted using isolated retinal immune cells. Results were reported as mean ± SEM, and statistical analyses were performed with GraphPad Prism (v8.0).

Results : In this study, we demonstrated that the absence of SOCS3 in myeloid cells led to a substantial accumulation of microglia during the neovascularization process. Our single-cell RNA sequencing data analysis has revealed a remarkable increase in secreted phosphoprotein 1 (Spp1) expression within certain subsets of microglia, leading to the identification of a novel subset of Spp1-expressing microglia during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia was elevated during neovascularization in mice lacking myeloid SOCS3. Furthermore, our investigation has unveiled Spp1 as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, the pharmaceutical activation of Socs3 or the inhibition of Spp1 resulted in a significant reduction in pathological neovascularization.

Conclusions : Our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.