Meningitic Escherichia coli Induction of ANGPTL4 in Brain Microvascular Endothelial Cells Contributes to Blood-Brain Barrier Disruption via ARHGAP5/RhoA/MYL5 Signaling Cascade.

Lu Liu,Zhong Peng,Huanchun Chen,Bo Yang,Ruicheng Yang,Jiyang Fu,Dong Huo,Bojie Xu,Jixuan Li,Xiangru Wang

doi:10.3390/pathogens8040254

Abstract

Bacterial meningitis is currently recognized as one of the most important life-threatening infections of the central nervous system (CNS) with high morbidity and mortality, despite the advancements in antimicrobial treatment. The disruption of blood–brain barrier (BBB) induced by meningitis bacteria is crucial for the development of bacterial meningitis. However, the complete mechanisms involving in the BBB disruption remain to be elucidated. Here, we found meningitic Escherichia coli induction of angiopoietin-like 4 (ANGPTL4) in brain microvascular endothelial cells (BMECs) contributes to BBB disruption via ARHGAP5/RhoA/MYL5 signaling cascade, by the demonstration that ANGPTL4 was significantly upregulated in meningitis E. coli infection of BMECs as well as mice, and treatment of the recombinant ANGPTL4 protein led to an increased permeability of the BBB in vitro and in vivo. Moreover, we found that ANGPTL4 did not affect the expression of tight junction proteins involved in BBB disruption, but it increased the expression of MYL5, which was found to have a negative role on the regulation of barrier function during meningitic E. coli infection, through the activation of RhoA signaling pathway. To our knowledge, this is the first report demonstrating the disruption of BBB induced by ANGPTL4 through the ARHGAP5/RhoA/MYL5 pathway, which largely supports the involvement of ANGPTL4 during meningitic E. coli invasion and further expands the theoretical basis for the mechanism of bacterial meningitis.

Highlights

Bacterial meningitis is recognized as one of the most important life-threatening infections of the central nervous system (CNS) with high morbidity and mortality, despite the advancements in antimicrobial treatment [1]
Via immunofluorescence (IF) assay, we demonstrated that the expression of angiopoietin-like 4 (ANGPTL4) protein was significantly increased in mouse brains along with the infection of meningitic E. coli (Figure 1)
ANGPTL4 was canonically regulated via the PPAR-associated pathways [19], and we investigated the possible involvement of PPAR transcriptional factors in human BMECs (hBMECs) upon the infection

Summary

Introduction

Bacterial meningitis is recognized as one of the most important life-threatening infections of the central nervous system (CNS) with high morbidity and mortality, despite the advancements in antimicrobial treatment [1]. Pathogens 2019, 8, 254 per year in developed countries and may be 10 times higher in less developed countries [2]. It estimates that the case fatality rates of the disease range from 5%–25%, and approximately 25%–50% of survivors sustain neurologic sequelae [3]. Despite its highly restrictive nature, certain bacterial pathogens, such as Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, and Escherichia coli, are able to gain entry into the CNS resulting in serious disease [9,10,11,12,13,14]

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Conclusion