IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients.
The contribution of inflammation to neurodegenerative diseases is increasingly recognized, but the role of inflammation in sporadic amyotrophic lateral sclerosis (sALS) is not well understood and no animal model is available. We used enzyme-linked immunosorbent assays (ELISAs) to measure the cytokine interleukin-17A (IL-17A) in the serum of ALS patients (n = 32; 28 sporadic ALS (sALS) and 4 familial ALS (fALS)) and control subjects (n = 14; 10 healthy subjects and 4 with autoimmune disorders). IL-17A serum concentrations were 5767 ± 2700 pg/ml (mean ± SEM) in sALS patients and 937 ± 927 pg/ml in fALS patients in comparison to 7 ± 2 pg/ml in control subjects without autoimmune disorders (p = 0.008 ALS patients vs. control subjects by Mann-Whitney test). Sixty-four percent of patients and no control subjects had IL-17A serum concentrations > 50 pg/ml (p = 0.003 ALS patients vs. healthy subjects by Fisher's exact test). The spinal cords of sALS (n = 8), but not control subjects (n = 4), were infiltrated by interleukin-1β- (IL-1β-), and tumor necrosis factor-α-positive macrophages (co-localizing with neurons), IL-17A-positive CD8 cells, and IL-17A-positive mast cells. Mononuclear cells treated with aggregated forms of wild type superoxide dismutase-1 (SOD-1) showed induction of the cytokines IL-1β, interleukin-6 (IL-6), and interleukin-23 (IL-23) that may be responsible for induction of IL-17A. In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects. Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons. Immune modulation of chronic inflammation may be a new approach to sALS.
Department of Medicine, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, 650 Charles E, Young Dr, South, Los Angeles, CA 90095-1735, USA. Fiala@mednet.ucla.edu
Milan
M
Fiala
Madhuri
M
Chattopadhay
Antonio
A
La Cava
Eric
E
Tse
Guanghao
G
Liu
Elaine
E
Lourenco
Ascia
A
Eskin
Philip T
PT
Liu
Larry
L
Magpantay
Stephen
S
Tse
Michelle
M
Mahanian
Rachel
R
Weitzman
Jason
J
Tong
Caroline
C
Nguyen
Tiffany
T
Cho
Patrick
P
Koo
James
J
Sayre
Otoniel
O
Martinez-Maza
Mark J
MJ
Rosenthal
Martina
M
Wiedau-Pazos
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020381:Interleukin-17 / Q000097:blood / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D008875:Middle Aged; D009154:Mutation; D013116:Spinal Cord / Q000166:cytology* / Q000276:immunology* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D016207:Cytokines; D020381:Interleukin-17; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1