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bioRxiv · 10.1101/2020.12.28.424586

Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice

Martino, N.·Bossardi Ramos, R.·Lu, S.·Leyden, K.·Tomaszek, L.·Jaitovich, A.·Vincent, P. A.·Adam, A. P.
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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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/424586v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@88eaf4org.highwire.dtl.DTLVardef@f974f1org.highwire.dtl.DTLVardef@16c9fa4org.highwire.dtl.DTLVardef@650229_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Martino, N., Bossardi Ramos, R., Lu, S., Leyden, K., Tomaszek, L., Jaitovich, A., Vincent, P. A., Adam, A. P.. 2020-12-28. Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice. https://doi.org/10.1101/2020.12.28.424586

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