Mimicry of Central-Peripheral Immunity in Alzheimer's Disease and Discovery of Neurodegenerative Roles in Neutrophil.

Joseph Park,Hansang Cho,Sung Hoon Baik,Inhee Mook-Jung,Daniel Irimia

doi:10.3389/fimmu.2019.02231

Abstract

Neuroinflammatory roles of central innate immunity in brain parenchyma are well-regarded in the progression of neurodegenerative disorders including Alzheimer's disease (AD), however, the roles of peripheral immunity in central nervous system (CNS) diseases are less clear. Here, we created a microfluidic environment of human AD brains: microglial neuroinflammation induced by soluble amyloid-beta (Abeta), a signature molecule in AD and employed the environment to investigate the roles of neutrophils through the central-peripheral innate immunity crosstalk. We observed that soluble Abeta-activated human microglial cells produced chemoattractants for neutrophils including IL6, IL8, CCL2, CCL3/4, CCL5 and consequently induced reliable recruitment of human neutrophils. Particularly, we validated the discernable chemo-attractive roles of IL6, IL8, and CCL2 for neutrophils by interrupting the recruitment with neutralizing antibodies. Upon recruitment, microglia-neutrophils interaction results in the production of inflammatory mediators such as MIF and IL2, which are known to up-regulate neuroinflammation in AD. We envision that targeting the crosstalk between central-peripheral immune community is a potential strategy to reduce immunological burdens in other neuroinflammatory CNS diseases.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia
A growing body of evidence suggests that neuroinflammation is the critical hallmark of AD and central innate immune cells have the major roles of neuroinflammation in a central nervous system (CNS) [6,7,8,9]
We established an in vitro system to study the crosstalk between microglia and neutrophils in the context of AD (Figure 1)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia. It affects more than 35 million people worldwide [1, 2]. It is characterized by neuropathological features including amyloid-beta (Abeta) plaques, neurofibrillary tangles, and neuroinflammation that lead into synaptic dysfunction and a progressive deterioration of cognitive functions [2,3,4,5]. Microglia, a macrophage resident in brains, produce both beneficial neuroinflammatory responses and detrimental neurotoxic effects in the progression of AD [10,11,12]. The regulation of microglial activation has been proposed as a potential therapeutic approach in AD treatment [13]

Methods

Results

Conclusion