Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice

Abstract 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...

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Bibliographic Details
Published inbioRxiv
Main Authors Martino, Nina, Ramos, Ramon Bossardi, Lu, Shuhan, Leyden, Kara, Tomaszek, Lindsay, Jaitovich, Ariel, Vincent, Peter A, Adam, Alejandro P
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 28.12.2020
Subjects
Cytokine storm
Endothelium
Homeostasis
Inflammation
Interferon
Interleukin 6
Lethal dose
Lipopolysaccharides
Phenotypes
Proteasomes
Proteins
Renal failure
Stat3 protein
Ubiquitination
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Summary:Abstract 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 non-lethal dose of lipopolysaccharide (LPS). SOCS3iEKO mice died 16-24 hours post-injection after severe kidney failure. Loss of SOCS3 led to an LPS-induced type I interferon-like program, and high expression of pro-thrombotic and pro-adhesive genes. Consistently, we observed intraluminal leukocyte adhesion and 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 HUVEC, pulse-chase experiments showed that SOCS3 protein has a half-life below 20 minutes. Inhibition of SOCS3 ubiquitination and proteasomal degradation leads to protein accumulation and a stronger inhibition of IL-6 signaling and barrier function loss. Together, our data demonstrates that the regulation of SOCS3 protein levels is critical to inhibit IL-6-mediated endotheliopathy during shock and provides a promising new therapeutic avenue to prevent MODS though stabilization of endothelial SOCS3. Figure1 Figure1 * Download figure * Open in new tab Competing Interest Statement The authors have declared no competing interest. Footnotes * Conflicts of Interest: The authors have declared that no conflict of interest exists. * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE163649
DOI:10.1101/2020.12.28.424586