Meningitic Escherichia coli K1 penetration and neutrophil transmigration across the blood-brain barrier are modulated by alpha7 nicotinic receptor.

Feng Chi,Ambrose Jong,Michael A Sheard,Xueye Zheng,Sheng-He Huang,Lin Wang,Wei Shi,Chun-Hua Wu,Samithamby Jeyaseelan

doi:10.1371/journal.pone.0025016

Abstract

Alpha7 nicotinic acetylcholine receptor (nAChR), an essential regulator of inflammation, is abundantly expressed in hippocampal neurons, which are vulnerable to bacterial meningitis. However, it is unknown whether α7 nAChR contributes to the regulation of these events. In this report, an aggravating role of α7 nAChR in host defense against meningitic E. coli infection was demonstrated by using α7-deficient (α7-/-) mouse brain microvascular endothelial cells (BMEC) and animal model systems. As shown in our in vitro and in vivo studies, E. coli K1 invasion and polymorphonuclear neutrophil (PMN) transmigration across the blood-brain barrier (BBB) were significantly reduced in α7-/- BMEC and α7-/- mice. Stimulation by nicotine was abolished in the α7-/- cells and animals. The same blocking effect was achieved by methyllycaconitine (α7 antagonist). The tight junction molecules occludin and ZO-1 were significantly reduced in the brain cortex of wildtype mice infected with E. coli and treated with nicotine, compared to α7-/- cells and animals. Decreased neuronal injury in the hippocampal dentate gyrus was observed in α7-/- mice with meningitis. Proinflammatory cytokines (IL-1β, IL-6, TNFα, MCP-1, MIP-1alpha, and RANTES) and adhesion molecules (CD44 and ICAM-1) were significantly reduced in the cerebrospinal fluids of the α7-/- mice with E. coli meningitis. Furthermore, α7 nAChR is the major calcium channel for nicotine- and E. coli K1-increased intracellular calcium concentrations of mouse BMEC. Taken together, our data suggest that α7 nAChR plays a detrimental role in the host defense against meningitic infection by modulation of pathogen invasion, PMN recruitment, calcium signaling and neuronal inflammation.

Highlights

Pathogen penetration and polymorphonuclear neutrophil (PMN) transmigration across the blood-brain barrier (BBB) are the hallmark features of bacterial meningitis, which is the most common serious infection of the central nervous system (CNS) [12]
In this report, using a7-deficient mouse cell culture and animal model systems, we examined how a7 nicotinic acetylcholine receptor (nAChR) contributed to the modulation of pathogen invasion, PMN recruitment and neuronal inflammation induced by E. coli K1, which is the most common gram-negative pathogen causing neonatal bacterial meningitis
We have established that a7 nAChR plays a detrimental role in host defense against bacterial meningitis in the mouse model

Summary

Introduction

Pathogen penetration and polymorphonuclear neutrophil (PMN) transmigration across the blood-brain barrier (BBB) are the hallmark features of bacterial meningitis, which is the most common serious infection of the central nervous system (CNS) [12]. We have previously shown that nicotine was able to enhance meningitic E. coli K1 invasion of human BMEC in vitro, suggesting the involvement of a7 nAChR in the pathogenesis of bacterial meningitis [8]. A number of the epidemiological studies have shown that exposure to passive tobacco smoke significantly increases the risk of bacteremia and bacterial meningitis [9,10,11], the pathogenic mechanisms of nicotine and tobacco smoke on this disease are largely unknown. This receptor is abundantly expressed in hippocampus, which is the region most vulnerable to bacterial meningitis. The prion protein (PrPc) could bind to a7 nAChR to form a signaling complex, which led to an increase in intracellular calcium and activation of ERK1/2 [19]

Methods

Results

Conclusion