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

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.

The Potential Role of Dysfunctions in Neuron-Microglia Communication in the Pathogenesis of Brain Disorders

“…The use of primary hippocampal neuronal cultures enabled the observation of the neuroprotective effect of CX3CL1 against glutamate-produced toxicity, which was possible due to the presence of extracellular adenosine [ 110 , 111 ]. The role of the CX3CL1-CX3CR1 axis in neuronal survival and neurotrophic effects in the CNS were also indicated by other research groups [ 43 , 98 , 112 - 114 ].…”

The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders

“…However, general information about the relevance of CX3CL1 and CX3CR1 in ALS is rather rare, except that disruption of MN-microglia communication as the result of CX3CR1 receptor deficiency in transgenic SOD1 G93A mice accelerates disease progression and exacerbates neuronal death [ 21 ]. This observation indicates that the protective role of CX3CR1 signaling has been proven [ 112 , 113 ]. In addition, CX3CR1 was postulated to be a potential gene that regulates the survival and progression of ALS [ 113 ].…”

“…Recent findings have confirmed that intercellular communication between motor neurons and microglia plays an important role in the pathogenesis of ALS [ 108 , 111 , 112 ]. The neuron–glia interaction was disrupted even before the onset of ALS symptoms.…”

Role of Microglial Cells in Alzheimer’s Disease Tau Propagation

“…Furthermore, it appears that the CX3CR1/CX3CL1 complex has also a neuroprotective effect while lacking either fractalkine (CX3CL1) or its receptor leads to neurodegeneration. Elevated microglia cell activation and neuronal loss have been also noticed in SOD1G93A/CX3CR1 −/− mice (Liu et al, 2019). One study showed that microglia can regulate the number of neural precursor cells in the developing brain.…”