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Role of endothelial SOCS3 in brain permeability and retinal vascular leukoembolization
Author(s) -
Lu Shuhan,
Martino Nina,
Bossardi Ramos Ramon,
Tomaszek Lindsay,
Adam Alejandro
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01791
Subject(s) - vascular permeability , cytokine , lipopolysaccharide , inflammation , socs3 , sepsis , endocrinology , medicine , systemic inflammation , evans blue , pharmacology , immunology , cancer , suppressor
Interleukin‐6 (IL‐6) is a major cytokine within the cytokine storm that occurs in response to severe systemic inflammation and sepsis. This cytokine promotes the activation of the JAK/STAT3 pathway. SOCS3, a protein induced by STAT3, acts as the main inhibitor this pathway. Prior work demonstrated that loss of SOCS3 in the endothelium of mice treated with LPS led to fast mortality within 16‐24 hours post‐challenge. The aim of this study is to determine the role of endothelial SOCS3 in brain permeability and retinal vascular leukoembolization in this severe, acute inflammatory model. We generated tamoxifen inducible SOCS3 knockout mice and induced severe acute inflammation by IP injection with LPS. Mice were evaluated for severity after 15 hours and euthanized for tissue collecting 16 hours after LPS injection. We found higher LPS‐induced severity in SOCS3iEKO mice compared to littermate controls. We observed significant weight loss after endotoxin, but surprisingly SOCS3iEKO mice displayed less weight loss, which could be due to fluid accumulation driven by increased systemic edema. Therefore, we interrogated whether SOCS3 loss promoted endothelial permeability. Lung and brain microvascular permeability was assayed by injecting FITC‐labeled 70kDa dextran 30 minutes prior to euthanasia and perfusion with PBS. Consistent with increased leakage, extravasated dextran was detected in thick (50‐100) um sections of LPS treated SOCS3iEKO mice. We hypothesized that this higher permeability could be due to increased leukocyte accumulation. In fact, we detected very high levels P‐selectin mRNA level in the kidneys, livers and lungs of LPS treated SOCS3iEKO mice, suggesting an increased adhesivity to leukocytes of the affected vasculature. To assess this, we stained flat mount retinas for P‐selectin and CD45 (pan‐leukocyte). LPS‐treated SOCS3iEKO mice showed a dramatic accumulation of intravascular leukocytes and increased P‐selectin expression. Intravascular leukocytes were also detected by standard H&E staining of lungs, livers and kidneys of SOCS3iEKO mice. In sum, we found that the lethality observed after a single endotoxin challenge in mice lacking endothelial SOCS3 is associated with increased intraluminal leukocyte adhesion and endothelial permeability.