TGFβ1 诱导的 hedgehog 信号通路抑制脑膜炎奈瑟菌引起的脑微血管内皮细胞免疫应答。

TGFβ1-induced hedgehog signaling suppresses the immune response of brain microvascular endothelial cells elicited by meningitic Escherichia coli.

机构信息

National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.

Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.

出版信息

Cell Commun Signal. 2024 Feb 15;22(1):123. doi: 10.1186/s12964-023-01383-y.

DOI:10.1186/s12964-023-01383-y

PMID:38360663

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10868028/

Abstract

BACKGROUND

Meningitic Escherichia coli (E. coli) is the major etiological agent of bacterial meningitis, a life-threatening infectious disease with severe neurological sequelae and high mortality. The major cause of central nervous system (CNS) damage and sequelae is the bacterial-induced inflammatory storm, where the immune response of the blood-brain barrier (BBB) is crucial.

METHODS

Western blot, real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and dual-luciferase reporter assay were used to investigate the suppressor role of transforming growth factor beta 1 (TGFβ1) in the immune response of brain microvascular endothelial cells elicited by meningitic E. coli.

RESULT

In this work, we showed that exogenous TGFβ1 and induced noncanonical Hedgehog (HH) signaling suppressed the endothelial immune response to meningitic E. coli infection via upregulation of intracellular miR-155. Consequently, the increased miR-155 suppressed ERK1/2 activation by negatively regulating KRAS, thereby decreasing IL-6, MIP-2, and E-selectin expression. In addition, the exogenous HH signaling agonist SAG demonstrated promising protection against meningitic E. coli-induced neuroinflammation.

CONCLUSION

Our work revealed the effect of TGFβ1 antagonism on E. coli-induced BBB immune response and suggested that activation of HH signaling may be a potential protective strategy for future bacterial meningitis therapy. Video Abstract.

摘要

背景

脑膜炎性大肠杆菌（E. coli）是细菌性脑膜炎的主要病原体，细菌性脑膜炎是一种危及生命的传染病，可导致严重的神经系统后遗症和高死亡率。中枢神经系统（CNS）损伤和后遗症的主要原因是细菌引发的炎症风暴，其中血脑屏障（BBB）的免疫反应至关重要。

方法

使用 Western blot、实时 PCR、酶联免疫吸附试验、免疫荧光和双荧光素酶报告基因检测，研究转化生长因子β 1（TGFβ1）在脑膜炎性大肠杆菌引起的脑微血管内皮细胞免疫反应中的抑制作用。

结果

在这项工作中，我们表明外源性 TGFβ1 和诱导的非经典 Hedgehog（HH）信号通过上调细胞内 miR-155 抑制内皮细胞对脑膜炎性大肠杆菌感染的免疫反应。因此，增加的 miR-155 通过负调控 KRAS 抑制 ERK1/2 的激活，从而降低 IL-6、MIP-2 和 E-选择素的表达。此外，外源性 HH 信号激动剂 SAG 对脑膜炎性大肠杆菌诱导的神经炎症具有显著的保护作用。