SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages

• DOI: 10.1016/j.ymthe.2024.03.025
• Publication Date: 2024-03-19T08:09:13Z
• Authors: Tianxi Wang; Satoshi Kaneko; Emil Kriukov; David Alvarez; Enton Lam; Yidi Wang; Sara La Manna; Daniela Marasco; Angeles Fernandez...; S. Alex Mitsialis; Stella Kourembanas; Andreas Stahl; Mei Chen; Heping Xu; Petr Baranov; Guoshuai Cai; Ulrich H. von And...; Ye Sun
• Keywords: STAT3 Transcription Factor; 610; microglia; Retinal Neovascularization; Mice; 03 medical and health sciences; retinopathy; Animals; SOCS3; neovascularization-associated microglia; Mice, Knockout; 0303 health sciences; Neovascularization, Pathologic; Macrophages; SOCS3; SPP1; macrophages; microglia; neovascularization; neovascularization-associated microglia; retinal angiogenesis; retinopathy; macrophages; Disease Models, Animal; Gene Expression Regulation; Suppressor of Cytokine Signaling 3 Protein; Osteopontin; Microglia; Angiogenesis; neovascularization; retinal angiogenesis; SPP1; Signal Transduction

Pathological ocular angiogenesis has long been associated with myeloid cell activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain elusive. In this study, we demonstrated that the absence of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells led to a substantial accumulation of microglia and macrophage subsets during the neovascularization process. Our single-cell RNA sequencing data analysis revealed a remarkable increase in the expression of the secreted phosphoprotein 1 (Spp1) gene within these microglia and macrophages, identifying subsets of Spp1-expressing microglia and macrophages during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia and macrophages exhibited further elevation during neovascularization in mice lacking myeloid SOCS3. Moreover, our investigation unveiled the Spp1 gene as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, pharmaceutical activation of SOCS3 or blocking of SPP1 resulted in a significant reduction in pathological neovascularization. In conclusion, our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis.