TY - JOUR
T1 - Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis
AU - Garofalo, Stefano
AU - Cocozza, Germana
AU - Porzia, Alessandra
AU - Inghilleri, Maurizio
AU - Raspa, Marcello
AU - Scavizzi, Ferdinando
AU - Aronica, Eleonora
AU - Bernardini, Giovanni
AU - Peng, Ling
AU - Ransohoff, Richard M.
AU - Santoni, Angela
AU - Limatola, Cristina
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85083545018&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-020-15644-8
DO - https://doi.org/10.1038/s41467-020-15644-8
M3 - Article
C2 - 32286313
SN - 2041-1723
VL - 11
SP - 1773
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1773
ER -