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

Mol Ther. 2024 May 1;32(5):1425-1444. doi: 10.1016/j.ymthe.2024.03.025. Epub 2024 Mar 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis
  • Animals
  • Disease Models, Animal*
  • Gene Expression Regulation
  • Macrophages* / metabolism
  • Mice
  • Mice, Knockout
  • Microglia* / metabolism
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Osteopontin* / genetics
  • Osteopontin* / metabolism
  • Retinal Neovascularization* / etiology
  • Retinal Neovascularization* / genetics
  • Retinal Neovascularization* / metabolism
  • Retinal Neovascularization* / pathology
  • STAT3 Transcription Factor* / genetics
  • STAT3 Transcription Factor* / metabolism
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein* / genetics
  • Suppressor of Cytokine Signaling 3 Protein* / metabolism


  • Suppressor of Cytokine Signaling 3 Protein
  • Socs3 protein, mouse
  • Osteopontin
  • STAT3 Transcription Factor
  • Spp1 protein, mouse