PMID- 34138760
OWN - NLM
STAT- MEDLINE
DCOM- 20220225
LR  - 20220225
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 6
IP  - 14
DP  - 2021 Jul 22
TI  - Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic 
      mice.
LID - 10.1172/jci.insight.147280 [doi]
LID - e147280
AB  - 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.
FAU - Martino, Nina
AU  - Martino N
AD  - Department of Molecular and Cellular Physiology.
FAU - Ramos, Ramon Bossardi
AU  - Ramos RB
AD  - Department of Molecular and Cellular Physiology.
FAU - Lu, Shuhan
AU  - Lu S
AD  - Department of Molecular and Cellular Physiology.
FAU - Leyden, Kara
AU  - Leyden K
AD  - Department of Molecular and Cellular Physiology.
FAU - Tomaszek, Lindsay
AU  - Tomaszek L
AD  - Department of Molecular and Cellular Physiology.
FAU - Sadhu, Sudeshna
AU  - Sadhu S
AD  - Department of Molecular and Cellular Physiology.
FAU - Fredman, Gabrielle
AU  - Fredman G
AD  - Department of Molecular and Cellular Physiology.
FAU - Jaitovich, Ariel
AU  - Jaitovich A
AD  - Department of Molecular and Cellular Physiology.
AD  - Division of Pulmonary and Critical Care Medicine, and.
FAU - Vincent, Peter A
AU  - Vincent PA
AD  - Department of Molecular and Cellular Physiology.
FAU - Adam, Alejandro P
AU  - Adam AP
AD  - Department of Molecular and Cellular Physiology.
AD  - Department of Ophthalmology, Albany Medical Center, Albany, New York, USA.
LA  - eng
GR  - K01 HL130704/HL/NHLBI NIH HHS/United States
GR  - R01 GM124133/GM/NIGMS NIH HHS/United States
GR  - R01 HL141127/HL/NHLBI NIH HHS/United States
GR  - R01 HL153019/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210722
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (SOCS3 protein, human)
RN  - 0 (Socs3 protein, mouse)
RN  - 0 (Suppressor of Cytokine Signaling 3 Protein)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Endothelium, Vascular/*pathology
MH  - Endotoxemia/diagnosis/*immunology/mortality/pathology
MH  - Heterozygote
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Interleukin-6/metabolism
MH  - Lipopolysaccharides/administration & dosage/immunology
MH  - Mice
MH  - Mice, Knockout
MH  - Proteolysis
MH  - Severity of Illness Index
MH  - Suppressor of Cytokine Signaling 3 Protein/analysis/genetics/*metabolism
MH  - Ubiquitination
PMC - PMC8410050
OTO - NOTNLM
OT  - Cytokines
OT  - Endothelial cells
OT  - Inflammation
OT  - Signal transduction
OT  - Vascular Biology
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2021/06/18 06:00
MHDA- 2022/02/26 06:00
PMCR- 2021/07/22
CRDT- 2021/06/17 17:20
PHST- 2020/12/29 00:00 [received]
PHST- 2021/06/16 00:00 [accepted]
PHST- 2021/06/18 06:00 [pubmed]
PHST- 2022/02/26 06:00 [medline]
PHST- 2021/06/17 17:20 [entrez]
PHST- 2021/07/22 00:00 [pmc-release]
AID - e147280 [pii]
AID - 147280 [pii]
AID - 10.1172/jci.insight.147280 [doi]
PST - epublish
SO  - JCI Insight. 2021 Jul 22;6(14):e147280. doi: 10.1172/jci.insight.147280.