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November 2019; 6 (6) ArticleOpen Access

IL6 receptor358Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis

Marlena Wosiski-Kuhn, Mac Robinson, Jane Strupe, Phonepasong Arounleut, Matthew Martin, James Caress, Michael Cartwright, Robert Bowser, Merit Cudkowicz, Carl Langefeld, Gregory A. Hawkins, Carol Milligan
First published October 14, 2019, DOI: https://doi.org/10.1212/NXI.0000000000000631
Marlena Wosiski-Kuhn
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Mac Robinson
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Jane Strupe
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Phonepasong Arounleut
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Matthew Martin
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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James Caress
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Michael Cartwright
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Robert Bowser
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Merit Cudkowicz
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Carl Langefeld
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Gregory A. Hawkins
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Carol Milligan
From the Department of Neurobiology and Anatomy (M.W.-K., M.R., J.S., P.A., M.M., C.M.); Department of Neurology (J.C., M. Cartwright); and Department of Biochemistry (G.A.H.), Wake Forest School of Medicine; Division of Public Health (C.L.), Department of Biostatistical Sciences, Wake Forest School of Medicine; Departments of Neurology and Neurobiology (R.B.), Barrow Neurological Institute & St. Joseph's Hospital and Medical Center; Department of Neurology (M. Cudkowicz), Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School; and Current Address Department of Pediatrics (M.M.), Nationwide Children's Hospital, Columbus OH.
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Full PDF
Citation
IL6 receptor358Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis
Marlena Wosiski-Kuhn, Mac Robinson, Jane Strupe, Phonepasong Arounleut, Matthew Martin, James Caress, Michael Cartwright, Robert Bowser, Merit Cudkowicz, Carl Langefeld, Gregory A. Hawkins, Carol Milligan
Neurol Neuroimmunol Neuroinflamm Nov 2019, 6 (6) e631; DOI: 10.1212/NXI.0000000000000631

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  • IL6 receptor358Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis - January 01, 2020
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    Figure 1 Subjects with amyotrophic lateral sclerosis (ALS) exhibit increased levels of interleukin 6 (IL6) in serum and CSF

    (A) Serum IL6 is significantly elevated in subjects with ALS compared with healthy controls (HCs) (p = 0.040, Cohen's D = 0.62) but not to disease controls (DCs) (p = 0.94) controls. (B) CSF IL6 is elevated in subjects with ALS compared with both HCs (p < 0.001, D = 0.61) and DCs (p = 0.021, D = 0.28). (C) Neither serum (ALS vs HC p = 0.30, vs DC p = 0.21) nor (D) CSF (ALS vs HC p = 0.32, vs DC p = 0.85) sIL6R varies with disease status. (E) Serum (ALS vs HC p = 0.28, vs DC p = 0.09) and (F) CSF sgp130 (ALS vs HC p = 0.18, vs DC p = 0.07) do not vary with disease status. (A) = p < 0.05, b = p < 0.001. For sgp130 and CSF IL6, all were planned comparisons where significance was determined by the Student t test. For serum IL6, significance was determined with generalized linear models, followed by Fisher protected least significant difference for planned individual comparisons of ALS vs HCs and ALS vs DCs; graphed values for IL6 are least squared means.

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    Figure 2 Interleukin 6 receptor (IL6R) C allele associates with serum levels of IL6R in all subjects, but only in patients with amyotrophic lateral sclerosis (ALS), does it account for CSF IL6R and IL6 increases

    (A) Concentrations of the sIL6R are significantly higher in subjects with the C allele compared with those without (p < 0.001, all groups). (B) CSF sIL6R are significantly increased only in subjects with ALS with the C allele compared with those without (CSF p = 0.021). (C) In serum, there is no significant difference in IL6 levels between subjects with ALS with and without the C allele; subjects with ALS with the C allele have more IL6 than healthy patients with the C allele (p = 0.045, D = 0.71). (D) Subjects with ALS with the C allele have more CSF IL6 than subjects with ALS without the C allele and than subjects with the C allele in the healthy control (HC) or disease control (DC) groups (p = 0.021, D = 0.56 compared with AA ALS; p < 0.001, D = 0.84, compared with *C HCs; p = 0.039, D = 0.18 compared with *C DCs). For serum and CSF sIL6R, and CSF IL6 all analyses were planned comparisons where significance was determined by the 2-sided Student t test. For serum IL6, significance was determined with generalized linear models, followed by Fisher protected least significant difference for planned individual comparisons of AA vs *C.

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    Figure 3 Subjects with amyotrophic lateral sclerosis (ALS) with the interleukin 6 receptor (IL6R) C allele have faster disease progression

    Subjects with ALS who are diagnosed within 12 months of symptom onset (table) who have the C allele lose more points on the ALSFRS-R between symptom onset and their first ALS clinic visit than those without the C allele. Results express as mean +SD; AA: n = 16; *C: n = 19; a = p = 0.019, D = 0.70; significance by Wilcoxon rank-sum.

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    Figure 4 In amyotrophic lateral sclerosis (ALS), interleukin 6 (IL6) trans-signaling effects on motor neurons may shift the balance from trophic activity to promoting a toxic environment

    In conditions of axonal injury, muscle injury, muscle stress (e.g., exercise), and atrophy (e.g., sarcopenia), increases in muscle-specific expression of IL6 are correlated with increased levels of circulating IL6.9,38,39 Of relevance to MNs, IL6 is a member of the CNTF/CT/LIF gp130 family of trophic factors that are critical in MN development and survival following injury and disease.7 In the local environment, in the presence of sIL6R, the myokine-receptor complex can bind to gp130 on MNs acting as a trophic factor. Accordingly, IL6 signaling may be beneficial in maintaining NMJ innervation, promoting MN survival, and rebuilding muscle (lower panel). Despite the potential prosurvival effect of IL6 on neurons in the periphery, it may be that in *C patients, CNS IL6 trans-signaling effects on glial cells promote damaging effects in the CNS.9,38,39 In the CNS, microglia become activated in response to NMJ denervation, and both microglial and astrocytes become active in response to disease-associated MN pathology. These and other CNS cells have been reported to be sources of IL6 (upper panel). In this central environment, IL6 can bind sIL6R and, as in the periphery, bind gp130 on MNs promoting trophic activity. However, the IL6-sIL6R complex can also bind to gp130 on glial cells to further activate them. In ALS, activated astrocytes have been shown to create a toxic environment for MNs.38,39 We hypothesize that this toxic activity overpowers any potential trophic activity, shifting the balance for MNs toward dysfunction and degeneration.

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