In:
International Archives of Allergy and Immunology, S. Karger AG, Vol. 183, No. 9 ( 2022), p. 997-1006
Abstract:
〈 b 〉 〈 i 〉 Purpose: 〈 /i 〉 〈 /b 〉 Vascular endothelial hyperpermeability and barrier disruption are involved in the initiation and development of sepsis. M1 macrophages promote inflammation in sepsis by releasing pro-inflammatory cytokines and chemokines. This study was designed to investigate the functional relationships between M1 macrophages and human umbilical vein endothelial cells (HUVECs), as well as the underlying molecular mechanisms. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 HUVECs were co-cultured with THP-1-derived M1 macrophages pretreated with or without rosiglitazone (RSG), a peroxisome proliferator-activated receptor (PPAR)-γ agonist. C-X-C chemokine receptor type (CXCR)5 was knocked down by short hairpin RNA lentivirus. Cecal ligation and puncture were used to induce sepsis in a mouse model. Endothelial permeability was evaluated using transendothelial electrical resistance and fluorescein isothiocyanate (FITC)-dextran assays. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Chemokine ligand (CXCL)13 was upregulated in M1 macrophages than M0 macrophages, as well as in the culture medium. In HUVECs co-cultured with M1 macrophages, transendothelial electrical resistance decreased, FITC-dextran flux increased, p38 phosphorylation was strengthened, and the expression of tight junction proteins (zonula occludens protein-1, occludin, and claudin-4) decreased. CXCR5 RNA interference or RSG pretreatment partially reversed these effects. A luciferase reporter assay revealed that CXCL13 was a direct target of PPAR-γ. RSG treatment decreased serum levels of creatinine, blood urea nitrogen, CXCL13, tumor necrosis factor-α, and interleukin-6, downregulated CXCL13 in peritoneal macrophages, and enhanced the survival rate of sepsis mice. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 M1 macrophages induced endothelial hyperpermeability and promoted p38 phosphorylation in sepsis by inhibiting PPAR-γ to increase CXCL13 production. PPAR-γ/CXCL13-CXCR5 signaling could be a promising novel therapeutic target for sepsis.
Type of Medium:
Online Resource
ISSN:
1018-2438
,
1423-0097
Language:
English
Publisher:
S. Karger AG
Publication Date:
2022
detail.hit.zdb_id:
1482722-0
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