Article Figures & Data
Figures
- 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.
- 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.
- 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.
- 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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