NK cells associate with ALS in a sex- and age-dependent manner.

Benjamin J Murdock,Caroline E Piecuch,Sebastian D Iniguez,Kristen D Raue,Stephen A Goutman,Cole H Pieroni,Eva L Feldman,Lili Zhao,Faye E Mendelson,Joshua P Famie,Kristen D Pawlowski

doi:10.1172/jci.insight.147129

Abstract

NK cells are innate immune cells implicated in ALS; whether NK cells impact ALS in a sex- and age-specific manner was investigated. Herein, NK cells were depleted in male and female SOD1G93A ALS mice, survival and neuroinflammation were assessed, and data were stratified by sex. NK cell depletion extended survival in female but not male ALS mice with sex-specific effects on spinal cord microglia. In humans, NK cell numbers, NK cell subpopulations, and NK cell surface markers were examined in prospectively blood collected from subjects with ALS and control subjects; longitudinal changes in these metrics were correlated to revised ALS functional rating scale (ALSFRS-R) slope and stratified by sex and age. Expression of NK cell trafficking and cytotoxicity markers was elevated in subjects with ALS, and changes in CXCR3+ NK cells and 7 trafficking and cytotoxicity markers (CD11a, CD11b, CD38, CX3CR1, NKG2D, NKp30, NKp46) correlated with disease progression. Age affected the associations between ALSFRS-R and markers NKG2D and NKp46, whereas sex impacted the NKp30 association. Collectively, these findings suggest that NK cells contribute to ALS progression in a sex- and age-specific manner and demonstrate that age and sex are critical variables when designing and assessing ALS immunotherapy.

Highlights

ALS is a lethal neurodegenerative disease characterized by progressive cortical and spinal motor neuron death, resulting in loss of voluntary motor control [1]
The present study examined whether NK cells contribute to ALS progression and whether this contribution is sex and age specific
Male ALS control mice had higher levels of microglia in the CNS than female ALS control mice; this was ameliorated by NK cell depletion

Summary

Introduction

ALS is a lethal neurodegenerative disease characterized by progressive cortical and spinal motor neuron death, resulting in loss of voluntary motor control [1]. NK cells are elevated in peripheral blood of subjects with ALS [4, 11], infiltrate the CNS of ALS mice and human subjects [12, 13], and drive proinflammatory microglial activity [13].

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