Peripheral Monocyte Entry Is Required for alpha-Synuclein Induced Inflammation and Neurodegeneration in a Model of Parkinson Disease

Exp Neurol. 2018 Feb;300:179-187. doi: 10.1016/j.expneurol.2017.11.010. Epub 2017 Nov 16.

Abstract

Accumulation of alpha-synuclein (α-syn) in the central nervous system (CNS) is a core feature of Parkinson disease (PD) that leads to activation of the innate immune system, production of inflammatory cytokines and chemokines, and subsequent neurodegeneration. Here, we used heterozygous reporter knock-in mice in which the first exons of the fractalkine receptor (CX3CR1) and of the C-C chemokine receptor type 2 (CCR2) are replaced with fluorescent reporters to study the role of resident microglia (CX3CR1+) and infiltrating peripheral monocytes (CCR2+), respectively, in the CNS. We used an α-syn mouse model induced by viral over-expression of α-syn. We find that in vivo, expression of full-length human α-syn induces robust infiltration of pro-inflammatory CCR2+ peripheral monocytes into the substantia nigra. Genetic deletion of CCR2 prevents α-syn induced monocyte entry, attenuates MHCII expression and blocks the subsequent degeneration of dopaminergic neurons. These results demonstrate that extravasation of pro-inflammatory peripheral monocytes into the CNS plays a key role in neurodegeneration in this model of PD synucleinopathy, and suggest that peripheral monocytes may be a target of neuroprotective therapies for human PD.

Keywords: C-C chemokine receptor type 2 (CCR2); Fractalkine receptor (CX3CR1) Major histocompatibility complex II (MHCII); Microglia; Monocytes; Parkinson disease (PD); α-syn (alpha-synuclein).

Publication types

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

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intermediate Filament Proteins / biosynthesis*
  • Intermediate Filament Proteins / toxicity
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / metabolism*
  • Monocytes / pathology
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / metabolism*
  • Parkinson Disease, Secondary / pathology

Substances

  • Intermediate Filament Proteins
  • desmuslin