The Mast Cell Is an Early Activator of Lipopolysaccharide-Induced Neuroinflammation and Blood-Brain Barrier Dysfunction in the Hippocampus.

Yiwei Wang,Leting Zhou,Yanning Qian,Hongquan Dong,Huanhuan Sha,Yinan Chen,Qin Zhou

doi:10.1155/2020/8098439

Abstract

Neuroinflammation contributes to or even causes central nervous system (CNS) diseases, and its regulation is thus crucial for brain disorders. Mast cells (MCs) and microglia, two resident immune cells in the brain, together with astrocytes, play critical roles in the progression of neuroinflammation-related diseases. MCs have been demonstrated as one of the fastest responders, and they release prestored and newly synthesized mediators including histamine, β-tryptase, and heparin. However, temporal changes in MC activation in this inflammation process remain unclear. This study demonstrated that MC activation began at 2 h and peaked at 4 h after lipopolysaccharide (LPS) administration. The number of activated MCs remained elevated until 24 h after LPS administration. In addition, the levels of histamine and β-tryptase in the hippocampus markedly and rapidly increased within 6 h and remained higher than the baseline level within 24 h after LPS challenge. Furthermore, mast cell-deficient KitW-sh/W-sh mice were used to investigate the effects of MCs on microglial and astrocytic activation and blood-brain barrier (BBB) permeability at 4 h after LPS stimulation. Notably, LPS-induced proinflammatory cytokine secretion, microglial activation, and BBB damage were inhibited in KitW-sh/W-sh mice. However, no detectable astrocytic changes were found in WT and KitW-sh/W-sh mice at 4 h after LPS stimulation. Our findings indicate that MC activation precedes CNS inflammation and suggest that MCs are among the earliest participants in the neuroinflammation-initiating events.

Highlights

The incidence of central nervous system (CNS) diseases is rapidly increasing worldwide, and neurological disorders are a significant global socioeconomic burden [1]
Our recent studies have highlighted the role of mast cells (MCs) in brain neuroinflammatory responses, and our findings indicate that significant elevations of MC number and degranulation are associated with postoperative cognitive dysfunction through microglial activation [10]
The results consistently showed that the number of MCs began to increase at 2 h, peaked at 4 h, and remained elevated until 24 h after LPS administration (Figures 1 and 2)

Summary

Introduction

The incidence of central nervous system (CNS) diseases is rapidly increasing worldwide, and neurological disorders are a significant global socioeconomic burden [1]. The mechanisms leading to CNS diseases are complex and are related to the brain function state and the insult severity. The neuroinflammatory response may be not an initiating factor in CNS diseases, emerging evidence indicates that sustained neuroinflammation contributes to the progression of CNS diseases [2], such as neurodegeneration, brain injury, and ischemic stroke, and is a crucial target for therapeutic strategies [3,4,5]. MCs in the CNS are typically found along cerebral blood vessels on the brain side of the blood-brain barrier (BBB). They are highly plastic cells derived from hematopoietic stem cells, and their

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