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Biol Chem. 2019 Apr 24;400(5):651-661. doi: 10.1515/hsz-2018-0204.

Evidence for a protective role of the CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis.

Liu C1,2, Hong K1, Chen H3, Niu Y2, Duan W4, Liu Y4, Ji Y1, Deng B1, Li Y4, Li Z4, Wen D1, Li C1,4,5.

Author information

1
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, People's Republic of China.
2
Department of Rehabilitation Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, People's Republic of China.
3
Department of Neurology, Hebei Province People's Hospital, Shijiazhuang 050000, Hebei, People's Republic of China.
4
Neurological Laboratory of Hebei Province, Shijiazhuang 050000, Hebei, People's Republic of China.
5
Institute of Cardiocerebrovascular Disease, West Heping Road 215, Shijiazhuang 050000, Hebei, People's Republic of China.

Abstract

Aberrant microglial activation and neuroinflammation is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Fractalkine (CX3CL1) is mostly expressed on neuronal cells. The fractalkine receptor (CX3CR1) is predominantly expressed on microglia. Many progressive neuroinflammatory disorders show disruption of the CX3CL1/CX3CR1 communication system. But the exact role of the CX3CL1/CX3CR1 in ALS pathology remains unknown. F1 nontransgenic/CX3CR1+/- females were bred with SOD1G93A/CX3CR1+/- males to produce F2 SOD1G93A/CX3CR1-/-, SOD1G93A/CX3CR1+/+. We analyzed end-stage (ES) SOD1G93A/CX3CR1-/- mice and progression-matched SOD1G93A/CX3CR1+/+ mice. Our study showed that the male SOD1G93A/CX3CR1-/- mice died sooner than male SOD1G93A/CX3CR1+/+ mice. In SOD1G93A/CX3CR1-/- mice demonstrated more neuronal cell loss, more microglial activation and exacerbated SOD1 aggregation at the end-stage of ALS. The NF-κB pathway was activated; the autophagy-lysosome degradation pathway and the autophagosome maturation were impaired. Our results indicated that the absence of CX3CR1/CX3CL1 signaling in the central nervous system (CNS) may worsen neurodegeneration. The CX3CL1/CX3CR1 communication system has anti-inflammatory and neuroprotective effects and plays an important role in maintaining autophagy activity. This effort may lead to new therapeutic strategies for neuroprotection and provide a therapeutic target for ALS patients.

KEYWORDS:

CX3CR1; amyotrophic lateral sclerosis (ALS); autophagy; inflammatory

PMID:
30352020
DOI:
10.1515/hsz-2018-0204

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