Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice

JCI Insight. 2021 Jul 22;6(14):e147280. doi: 10.1172/jci.insight.147280.


SOCS3 is the main inhibitor of the JAK/STAT3 pathway. This pathway is activated by interleukin 6 (IL-6), a major mediator of the cytokine storm during shock. To determine its role in the vascular response to shock, we challenged mice lacking SOCS3 in the adult endothelium (SOCS3iEKO) with a nonlethal dose of lipopolysaccharide (LPS). SOCS3iEKO mice died 16-24 hours postinjection after severe kidney failure. Loss of SOCS3 led to an LPS-induced type I IFN-like program and high expression of prothrombotic and proadhesive genes. Consistently, we observed intraluminal leukocyte adhesion and neutrophil extracellular trap-osis (NETosis), as well as retinal venular leukoembolization. Notably, heterozygous mice displayed an intermediate phenotype, suggesting a gene dose effect. In vitro studies were performed to study the role of SOCS3 protein levels in the regulation of the inflammatory response. In human umbilical vein endothelial cells, pulse-chase experiments showed that SOCS3 protein had a half-life less than 20 minutes. Inhibition of SOCS3 ubiquitination and proteasomal degradation led to protein accumulation and a stronger inhibition of IL-6 signaling and barrier function loss. Together, our data demonstrate that the regulation of SOCS3 protein levels is critical to inhibit IL-6-mediated endotheliopathy during shock and provide a promising therapeutic avenue to prevent multiorgan dysfunction through stabilization of endothelial SOCS3.

Keywords: Cytokines; Endothelial cells; Inflammation; Signal transduction; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endothelium, Vascular / pathology*
  • Endotoxemia / diagnosis
  • Endotoxemia / immunology*
  • Endotoxemia / mortality
  • Endotoxemia / pathology
  • Heterozygote
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / immunology
  • Mice
  • Mice, Knockout
  • Proteolysis
  • Severity of Illness Index
  • Suppressor of Cytokine Signaling 3 Protein / analysis
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / metabolism*
  • Ubiquitination


  • Interleukin-6
  • Lipopolysaccharides
  • SOCS3 protein, human
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein