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Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis.

ABSTRACT: In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1^G93A, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43^A315T. NK cells are neurotoxic to hSOD1^G93A MNs which express NKG2D ligands, while IFN? produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3⁺/Treg cell infiltration in the spinal cord of hSOD1^G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.

SUBMITTER: Garofalo S

PROVIDER: S-EPMC7156729 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis.

Garofalo Stefano S Cocozza Germana G Porzia Alessandra A Inghilleri Maurizio M Raspa Marcello M Scavizzi Ferdinando F Aronica Eleonora E Bernardini Giovanni G Peng Ling L Ransohoff Richard M RM Santoni Angela A Limatola Cristina C

Nature communications 20200414 1

In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1<sup>G93A</sup>, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increa ...[more]

PMID: 32286313

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Project description:BackgroundAmyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND.ObjectivesTo assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment.Search methodsOn 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies.Selection criteriaWe planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally.Data collection and analysisWe followed standard Cochrane methodology.Main resultsNo studies were eligible for inclusion in the review. We identified four ongoing trials.Authors' conclusionsCurrently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.

Dataset Information

Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis.

Publications

Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis.

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