Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models
<b>Background/Objectives:</b> Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic association...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Brain Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3425/15/1/84 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588883120881664 |
|---|---|
| author | Carol Milligan Dale O. Cowley William Stewart Alyson M. Curry Elizabeth Forbes Brian Rector Annette Hastie Liang Liu Gregory A. Hawkins |
| author_facet | Carol Milligan Dale O. Cowley William Stewart Alyson M. Curry Elizabeth Forbes Brian Rector Annette Hastie Liang Liu Gregory A. Hawkins |
| author_sort | Carol Milligan |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. <b>Methods:</b> We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred <i>SOD1<sup>G93A</sup></i> mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. <b>Results:</b> The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. <b>Conclusions:</b> Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common <i>Il6R</i> Asp<sup>358</sup>Ala variant. |
| format | Article |
| id | doaj-art-1187991403d24ae9a67ac8a8c68127c1 |
| institution | Kabale University |
| issn | 2076-3425 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Brain Sciences |
| spelling | doaj-art-1187991403d24ae9a67ac8a8c68127c12025-01-24T13:25:55ZengMDPI AGBrain Sciences2076-34252025-01-011518410.3390/brainsci15010084Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse ModelsCarol Milligan0Dale O. Cowley1William Stewart2Alyson M. Curry3Elizabeth Forbes4Brian Rector5Annette Hastie6Liang Liu7Gregory A. Hawkins8Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Genetics and Animal Models Core Facility, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Internal Medicine Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Internal Medicine Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA<b>Background/Objectives:</b> Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. <b>Methods:</b> We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred <i>SOD1<sup>G93A</sup></i> mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. <b>Results:</b> The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. <b>Conclusions:</b> Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common <i>Il6R</i> Asp<sup>358</sup>Ala variant.https://www.mdpi.com/2076-3425/15/1/84motor neuron diseaseneuroimmuneglial cellsneuromuscular junctionsmicrogliaastrocytes |
| spellingShingle | Carol Milligan Dale O. Cowley William Stewart Alyson M. Curry Elizabeth Forbes Brian Rector Annette Hastie Liang Liu Gregory A. Hawkins Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models Brain Sciences motor neuron disease neuroimmune glial cells neuromuscular junctions microglia astrocytes |
| title | Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models |
| title_full | Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models |
| title_fullStr | Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models |
| title_full_unstemmed | Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models |
| title_short | Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models |
| title_sort | enhanced interleukin 6 trans signaling modulates disease process in amyotrophic lateral sclerosis mouse models |
| topic | motor neuron disease neuroimmune glial cells neuromuscular junctions microglia astrocytes |
| url | https://www.mdpi.com/2076-3425/15/1/84 |
| work_keys_str_mv | AT carolmilligan enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT daleocowley enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT williamstewart enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT alysonmcurry enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT elizabethforbes enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT brianrector enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT annettehastie enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT liangliu enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels AT gregoryahawkins enhancedinterleukin6transsignalingmodulatesdiseaseprocessinamyotrophiclateralsclerosismousemodels |