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

Stefano Garofalo,Germana Cocozza,Giovanni Bernardini,Ling Peng,Eleonora Aronica,Richard M Ransohoff,Angela Santoni,Cristina Limatola,Maurizio Inghilleri,Marcello Raspa,Ferdinando Scavizzi,Alessandra Porzia

doi:10.1038/s41467-020-15644-8

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, hSOD1G93A, 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, TDP43A315T. NK cells are neurotoxic to hSOD1G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3+/Treg cell infiltration in the spinal cord of hSOD1G93A 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.

Highlights

In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration
NKp46+ cells were detected in sALS spinal cord and cerebral motor cortex postmortem tissues while they were not observed in the spinal cord or motor cortex of controls
NK cells isolated from the spleen and the spinal cord of wt and hSOD1G93A mice were analysed for the expression of activation markers and cytotoxic factors CD69, Granzyme b (GZMb) and perforin (PRF)

Summary

Introduction

In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. NK cells are neurotoxic to hSOD1G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3+/Treg cell infiltration in the spinal cord of hSOD1G93A 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. In a subgroup of familial ALS (fALS), mutant superoxide dismutase 1 (SOD1) is expressed In this form of ALS and in the corresponding mouse models, microglia acquire an inflammatory phenotype, affecting MN death[2,3], and myeloid cells expressing mutated SOD1 promote neurotoxicity[4,5].

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