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

• Published in: Nature communications 2020-04, Vol.11 (1), p.1773-16, Article 1773
• Main Authors: Garofalo, Stefano, Cocozza, Germana, Porzia, Alessandra, Inghilleri, Maurizio, Raspa, Marcello, Scavizzi, Ferdinando, Aronica, Eleonora, Bernardini, Giovanni, Peng, Ling, Ransohoff, Richard M., Santoni, Angela, Limatola, Cristina
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 13/51; 13/89; 14; 14/19; 38; 38/77; 631/378/1689/1285; 631/378/371; 96; Adult; Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - immunology; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animal models; Animals; Cell culture; Cellular Biology; Cortex (motor); Crosstalk; Degeneration; Depletion; Disease Models, Animal; Disease Progression; Female; Foxp3 protein; Humanities and Social Sciences; Humans; Immune system; Immunology; Inflammation; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Life Sciences; Ligands; Lymphocytes T; Male; Mice; Microglia; Middle Aged; Monocyte chemoattractant protein 1; Motor Cortex - immunology; Motor Cortex - metabolism; Motor Cortex - pathology; Motor Neurons - immunology; Motor Neurons - metabolism; Motor Neurons - pathology; multidisciplinary; Natural Cytotoxicity Triggering Receptor 1 - genetics; Natural Cytotoxicity Triggering Receptor 1 - metabolism; Natural killer cells; Neuronal-glial interactions; Neurotoxicity; NKG2 antigen; Phenotypes; Science; Science (multidisciplinary); Spinal cord; Spinal Cord - immunology; Spinal Cord - metabolism; Spinal Cord - pathology; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15644-8

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 IFNγ 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. Neuroimmune interactions are important in amyotrophic lateral sclerosis (ALS). Here the authors characterize the role of NK cells in mouse models of ALS, and in patient tissue.