CXCL13 Is Involved in the Lipopolysaccharide-Induced Hyperpermeability of Umbilical Vein Endothelial Cells

Abstract

Sepsis is a disease that is characterized by a severe systemic inflammatory response to microbial infection and lipopolysaccharide (LPS) and is a well-known inducer of sepsis, as well as endothelial cell hyperpermeability. In the present study, we confirm the elevation of CXC chemokine ligand 13 (CXCL13) in sepsis patients. We also show that LPS exposure increases the release of CXCL13, as well as the mRNA and protein expression of CXCL13 and its receptor, CXC chemokine receptor 5 (CXCR5) in human umbilical vein endothelial cells (HUVECs) in a dose-and time-dependent manner. We also examined the effects of CXCL13 knockdown on LPS-mediated endothelial hyperpermeability and tight junction (TJ) protein expression in HUVECs. Our results show that HUVECs exposed to LPS result in a significant decrease in transendothelial electrical resistance (TER) and TJ protein (Zonula occluden-1, occludin, and claudin-4) expression, and a notable increase in fluorescein isothiocyanate (FITC)-dextran flux and p38 phosphorylation, which was partially reversed by CXCL13 knockdown. Recombinant CXCL13 treatment had a similar effect as LPS exposure, which was attenuated by a p38 inhibitor, SB203580. Moreover, the CXCL13neutralizing antibody significantly increased the survival rate of LPS-induced sepsis mice. Collectively, our results show that CXCL13 plays a key role in LPS-induced endothelium hyperpermeability via regulating p38 signaling and suggests that therapeutically targeting CXCL13 may be beneficial for the treatment of sepsis.

CXCR5 down-regulation alleviates cognitive dysfunction in a mouse model of sepsis-associated encephalopathy: potential role of microglial autophagy and the p38MAPK/NF-κB/STAT3 signaling pathway

“…Sepsis in neonatal rats has been shown to activate p38MAPK signaling in the brain, and the p38MAPK inhibitor SB203580 can protect against sepsis-associated cognitive deficits [44]. CXCL13 level was increased in the serum of patients with sepsis, and CXCL13 also acts via p38MAPK signaling to drive LPS-induced hyperpermeability of the endothelium in human umbilical vein endothelial cells, suggesting that targeting CXCL13 may alleviate sepsis [45]. Similarly, p38MAPK mediates LPSinduced morphological changes and production of IL-1β in primary microglial cultures and the brain [24], and it contributes to acute lung injury in a mouse model by stimulating autophagy, oxidative stress and inflammatory responses [46].…”

CXCR5 Down-regulation Alleviates Cognitive Dysfunction in a Mouse Model of Sepsis-associated Encephalopathy: Potential Role of Neuronal Autophagy and the p38MAPK/NF-κB/STAT3 Signaling Pathway

“…Sepsis in neonatal rats has been shown to activate p38MAPK signaling in the brain, and the p38MAPK inhibitor SB203580 can protect against sepsis-associated cognitive de cits [44]. CXCL13 level was increased in the serum of patients with sepsis, and CXCL13 also acts via p38MAPK signaling to drive LPS-induced hyperpermeability of the endothelium in human umbilical vein endothelial cells, suggesting that targeting CXCL13 may alleviate sepsis [45]. Similarly, p38MAPK mediates LPS-induced morphological changes and production of IL-1β in primary microglial cultures and the brain [24], and it contributes to acute lung injury in a mouse model by stimulating autophagy, oxidative stress and in ammatory responses [46].…”

Zanthoxylum nitidum extract attenuates BMP-2-induced inflammation and hyperpermeability

“…As a result, the permeability of the monolayer of HUVECs was protected. Moreover, the dextran assay (Transwell-experiment with dextran) is typically utilized to evaluate the permeability of cells [ 44 , 45 ]. In our work, we performed the dextran assay in each experiment group.…”