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

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

  • Cell Commun Signal. 2024 Feb 15;22(1):123. doi: 10.1186/s12964-023-01383-y.
Jinrui Sun # 1 2,  Ruicheng Yang # 1 2,  Jiyang Fu # 1 2,  Dong Huo 1 2,  Xinyi Qu 1 2,  Chen Tan 1 2 3 4,  Huanchun Chen 1 2 3 4,  Xiangru Wang 5 6 7 8
Affiliations

Affiliations

  • 1 National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
  • 2 Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
  • 3 Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, 430070, China.
  • 4 International Research Center for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, 430070, China.
  • 5 National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China. wangxr228@mail.hzau.edu.cn.
  • 6 Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China. wangxr228@mail.hzau.edu.cn.
  • 7 Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, 430070, China. wangxr228@mail.hzau.edu.cn.
  • 8 International Research Center for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, 430070, China. wangxr228@mail.hzau.edu.cn.
  • # Contributed equally.
PMID: 38360663 DOI: 10.1186/s12964-023-01383-y
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.

Keywords

Brain microvascular endothelial cells; Escherichia coli; Hedgehog signaling; Neuroinflammation; SAG; TGFβ1; miR-155.

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