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

Tianxi Wang; Satoshi Kaneko; Emil Kriukov; David Alvarez; Enton Lam; Yidi Wang; Sara La Manna; Daniela Marasco; Angeles Fernandez-Gonzalez; S Alex Mitsialis; Stella Kourembanas; Andreas Stahl; Mei Chen; Heping Xu; Petr Baranov; Guoshuai Cai; Ulrich H von Andrian; Ye Sun

doi:10.1016/j.ymthe.2024.03.025

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

Mol Ther. 2024 Mar 19:S1525-0016(24)00166-7. doi: 10.1016/j.ymthe.2024.03.025. Online ahead of print.

Authors

Tianxi Wang¹, Satoshi Kaneko¹, Emil Kriukov², David Alvarez³, Enton Lam¹, Yidi Wang³, Sara La Manna⁴, Daniela Marasco⁴, Angeles Fernandez-Gonzalez⁵, S Alex Mitsialis⁵, Stella Kourembanas⁵, Andreas Stahl⁶, Mei Chen⁷, Heping Xu⁷, Petr Baranov², Guoshuai Cai⁸, Ulrich H von Andrian⁹, Ye Sun¹⁰

Affiliations

¹ Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Department of Ophthalmology, The Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA.
³ Department of Immunology and HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Pharmacy, University of Naples "Federico II", 80138 Naples, Italy.
⁵ Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Ophthalmology, University Medicine Greifswald, 17475 Greifswald, Germany.
⁷ Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
⁸ Department of Surgery, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
⁹ Department of Immunology and HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA; The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
¹⁰ Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ye.sun@childrens.harvard.edu.

PMID: 38504518
DOI: 10.1016/j.ymthe.2024.03.025

Abstract

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.

Keywords: SOCS3; SPP1; macrophages; microglia; neovascularization; neovascularization-associated microglia; retinal angiogenesis; retinopathy.

Abstract

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