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Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice
Nina Martino, … , Peter A. Vincent, Alejandro P. Adam
Nina Martino, … , Peter A. Vincent, Alejandro P. Adam
Published June 17, 2021
Citation Information: JCI Insight. 2021;6(14):e147280. https://doi.org/10.1172/jci.insight.147280.
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Research Article Inflammation Vascular biology

Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice

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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 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.

Authors

Nina Martino, Ramon Bossardi Ramos, Shuhan Lu, Kara Leyden, Lindsay Tomaszek, Sudeshna Sadhu, Gabrielle Fredman, Ariel Jaitovich, Peter A. Vincent, Alejandro P. Adam

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Figure 7

IL-6–induced gene expression profile in HUVECs.

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IL-6–induced gene expression profile in HUVECs.
(A) Heatmap and unbiased...
(A) Heatmap and unbiased clustering of cells treated with either PBS or IL-6+R after 30-minute incubation with either rux or DMSO (vehicle control). Ribosomal RNA–depleted RNA was assayed by RNA sequencing. Shown are the 50 most significant differences between IL-6+R and PBS, sorted by log2 fold change difference. One experiment performed in triplicate. (B) RT-qPCR analysis of an IL-6+R time course to confirm the changes in mRNA expression of selected candidate genes. One-way ANOVA and Dunnett’s post hoc (vs. no IL-6+R, n = 6). Combined data from 3 independent experiments each performed in duplicate. (C) ISMARA of gene expression changes using the FASTQ files obtained in A showing a significant enrichment in type I interferon responses. (D) STRING representation of the main interconnections of genes identified in C. (E) RT-qPCR of cells treated with or without IL-6+R after infection with lentivirus to overexpress WT-SOCS3 or K6Q-SOCS3. An empty vector lentivirus was used as control. Two-way ANOVA and Dunnett’s post hoc tests (n = 4–6). Combined data from 3 independent experiments each performed in duplicate. Asterisks denote P < 0.05. RHOU, ras homolog family member U; PTGS2, prostaglandin-endoperoxide synthase 2; MX1, MX dynamin like GTPase 1.

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