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

Front Immunol. 2019 Sep 25;10:2231. doi: 10.3389/fimmu.2019.02231. eCollection 2019.

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.

Keywords: Alzheimer's disease; cellular interaction; chemotaxis; microfluidics; microglia; neurodegeneration; neuroinflammation; neutrophil.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / immunology*
  • Amyloid beta-Peptides / immunology
  • Antibodies, Neutralizing / immunology
  • Cell Line
  • Humans
  • Immunity, Innate / immunology
  • Inflammation / immunology
  • Microglia / immunology
  • Neurodegenerative Diseases / immunology*
  • Neutrophils / immunology*
  • Up-Regulation / immunology

Substances

  • Amyloid beta-Peptides
  • Antibodies, Neutralizing