Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice
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 nonletha...
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Published in | JCI insight Vol. 6; no. 14 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Society for Clinical Investigation
22.07.2021
American Society for Clinical investigation |
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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. |
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AbstractList | 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. 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 (SOCS3 iEKO ) with a nonlethal dose of lipopolysaccharide (LPS). SOCS3 iEKO 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. |
Author | Lu, Shuhan Vincent, Peter A Tomaszek, Lindsay Adam, Alejandro P Ramos, Ramon Bossardi Jaitovich, Ariel Fredman, Gabrielle Martino, Nina Leyden, Kara Sadhu, Sudeshna |
AuthorAffiliation | 1 Department of Molecular and Cellular Physiology 2 Division of Pulmonary and Critical Care Medicine, and 3 Department of Ophthalmology, Albany Medical Center, Albany, New York, USA |
AuthorAffiliation_xml | – name: 1 Department of Molecular and Cellular Physiology – name: 3 Department of Ophthalmology, Albany Medical Center, Albany, New York, USA – name: 2 Division of Pulmonary and Critical Care Medicine, and |
Author_xml | – sequence: 1 givenname: Nina surname: Martino fullname: Martino, Nina organization: Department of Molecular and Cellular Physiology – sequence: 2 givenname: Ramon Bossardi surname: Ramos fullname: Ramos, Ramon Bossardi organization: Department of Molecular and Cellular Physiology – sequence: 3 givenname: Shuhan surname: Lu fullname: Lu, Shuhan organization: Department of Molecular and Cellular Physiology – sequence: 4 givenname: Kara surname: Leyden fullname: Leyden, Kara organization: Department of Molecular and Cellular Physiology – sequence: 5 givenname: Lindsay surname: Tomaszek fullname: Tomaszek, Lindsay organization: Department of Molecular and Cellular Physiology – sequence: 6 givenname: Sudeshna surname: Sadhu fullname: Sadhu, Sudeshna organization: Department of Molecular and Cellular Physiology – sequence: 7 givenname: Gabrielle surname: Fredman fullname: Fredman, Gabrielle organization: Department of Molecular and Cellular Physiology – sequence: 8 givenname: Ariel surname: Jaitovich fullname: Jaitovich, Ariel organization: Division of Pulmonary and Critical Care Medicine, and – sequence: 9 givenname: Peter A surname: Vincent fullname: Vincent, Peter A organization: Department of Molecular and Cellular Physiology – sequence: 10 givenname: Alejandro P surname: Adam fullname: Adam, Alejandro P organization: Department of Ophthalmology, Albany Medical Center, Albany, New York, USA |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34138760$$D View this record in MEDLINE/PubMed |
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Keywords | Signal transduction Inflammation Cytokines Vascular Biology Endothelial cells |
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SubjectTerms | Animals Disease Models, Animal Endothelium, Vascular - pathology Endotoxemia - diagnosis Endotoxemia - immunology Endotoxemia - mortality Endotoxemia - pathology Heterozygote Human Umbilical Vein Endothelial Cells Humans Inflammation 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 Vascular biology |
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Title | Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice |
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