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

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 SOD1(G93A)/CX3CR1(+/-) males to produce F2 SOD1(G93A)/CX3CR1(-/-), SOD1(G93A)/CX3CR1(+/+). We analyzed end-stage (ES) SOD1(G93A)/CX3CR1(-/-) mice and progression-matched SOD1(G93A)/CX3CR1(+/+) mice. Our study showed that the male SOD1(G93A)/CX3CR1(-/-) mice died sooner than male SOD1(G93A)/CX3CR1(+/+) mice. In SOD1(G93A)/CX3CR1(-/-) mice demonstrated more neuronal cell loss, more microglial activation and exacerbated SOD1 aggregation at the end-stage of ALS. The NF-kappa B 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.