NK cells associate with ALS in a sex- and age-dependent manner
Benjamin J. Murdock, … , Stephen A. Goutman, Eva L. Feldman
Benjamin J. Murdock, … , Stephen A. Goutman, Eva L. Feldman
Published May 11, 2021
Citation Information: JCI Insight. 2021;6(11):e147129. https://doi.org/10.1172/jci.insight.147129.
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Research Article Immunology Neuroscience

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

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.

Authors

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

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Figure 1

Effects of NK1.1+ NK cell depletion on ALS mice.

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Effects of NK1.1+ NK cell depletion on ALS mice. (A) SOD1G93A ALS mice w...
(A) SOD1G93A ALS mice were treated with an initial intraperitoneal dose of 500 μg NK cell depleting antibody and subsequent weekly boosters of 150 μg (ALS treatment, blue); a control group of ALS mice was treated with a nonspecific IgG sham treatment (ALS control, red). Both were compared with WT mice (black) mice. Time on rotarod and forelimb grip strength was examined at 9, 10, 14, 18, 21, and 23 weeks of age. (B) Levels of NK1.1+ NK cells were examined in the peripheral blood of WT (n = 6), ALS control (n = 9), and ALS treatment (n = 7) mice, and (C) in the spinal cord (WT, n = 6; ALS control, n = 10; ALS treatment, n = 10) using flow cytometry at the terminal disease endpoint. Blood levels were compared using Kruskal-Wallis due to non-normal distribution, and spinal cord levels using ANOVA. (D) Mouse survival was analyzed using Kaplan-Meier to compare WT, ALS control, and ALS treatment mice. (E) Fold change in weight, (F) grip strength (normalized to body weight), and (G) time on a rotarod were analyzed at regular intervals for WT (black; n = 6), ALS control (red; n = 11), and ALS treatment (blue; n = 12) mice. Data at each time point were analyzed using 2-way ANOVA with multiple comparisons. Mean and SEM are displayed. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.