Abstract
Bacterial meningitis is a life-threatening infectious disease with high morbidity and mortality worldwide, among which meningitic Escherichia coli is a common Gram-negative pathogenic bacterium causing meningitis. It can penetrate the blood–brain barrier (BBB), invoke local inflammatory responses and consequently disrupt the integrity of the BBB. Interleukin-17A (IL-17A) is recognized as a pro-inflammatory cytokine that is released during meningitic E. coli infection. It has been reported that IL-17A is involved in several pathological tissue injuries. However, the function of IL-17A in BBB breakdown remains rarely discussed. Here, our study found that E. coli-induced IL-17A led to the degradation of tight junction proteins (TJs) and adherens junction proteins (AJs) in human brain microvascular endothelial cells (hBMECs) through inhibiting protease proteinase 3 (PRTN3)/protease-activated receptor 2 (PAR-2) axis, thus increasing the permeability of BBB. In summary, this study uncovered the involvement of IL-17A in regulating BBB integrity and proposed a novel regulatory mechanism, which could be potential therapeutic targets of E. coli meningitis.
Highlights
Bacterial meningitis is a severe life-threatening infectious disease of the central nervous system (CNS) and a major cause of death or disability worldwide, especially in newborns (Leib and Tauber, 1999)
These findings suggested that meningitic E. coli infection in mice can cause a significant increase of IL17A in the brain
Since a high level of IL-17A was detected in mouse brains after E. coli infection, we investigated the function of IL-17A in regulating blood–brain barrier (BBB) permeability
Summary
Bacterial meningitis is a severe life-threatening infectious disease of the central nervous system (CNS) and a major cause of death or disability worldwide, especially in newborns (Leib and Tauber, 1999). Blood–brain barrier is a microvasculature that coordinates the movement of molecules and cells between the CNS and bloodstream (Zlokovic, 2008) It comprises brain microvascular endothelial cells (BMECs), pericytes, and astrocyte endfeet and maintains CNS homeostasis (Hawkins and Davis, 2005). Increased BBB permeability has been reported in numerous diseases, such as neoplasia, hypertension, experimental allergic encephalomyelitis, trauma, and neurotropic viral infections (Scholz et al, 2007; CandelarioJalil et al, 2009) Inflammatory factors such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), C-C motif ligand 2 (CCL2, known as MCP-1) are reported to mediate BBB breakdown, which leads to the infiltration of peripheral leukocytes and brain injury (Sarami Foroshani et al, 2018; Siqueira et al, 2021; Xu D. et al, 2021). The underlying mechanisms by which these factors regulate BBB permeability in response to infection remain largely unclear
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