The Impact of Interleukin-6 (IL-6) and Mesenchymal Stem Cell-derived IL-6 on Neurological Conditions

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Jul 17

PMID 39015561

Authors

Irina Kerkis

Alvaro Prieto da Silva

Rodrigo Pinheiro Araldi

Affiliations

Soon will be listed here.

Abstract

Interleukin-6 (IL-6) is a versatile cytokine crucial for immune response modulation, inflammation regulation, and various physiological processes in the body. Its wide-ranging functions underscore its importance in maintaining health. Dysregulated IL-6 is closely associated with many diseases, making it a key research and therapeutic target. Elevated IL-6 levels in the central nervous system worsen neuroinflammation in neurodegenerative diseases by activating microglia and astrocytes and releasing pro-inflammatory cytokines and neurotoxic molecules. Moreover, dysregulated IL-6 weakens the blood-brain barrier, exacerbating neuroinflammation and neuronal damage by allowing peripheral immune cells and inflammatory mediators to enter the brain. Mesenchymal stem cells (MSCs) show promise in modulating neuroinflammation by regulating IL-6 levels. They effectively suppress pro-inflammatory cytokines, including IL-6, while promoting anti-inflammatory factors. This therapeutic approach highlights the importance of targeting IL-6 and other inflammatory mediators to alleviate neuroinflammation and its adverse effects on neurological disorders. This review provides a comprehensive overview of IL-6's involvement in neurological disorders, examining endogenous IL-6 and IL-6 derived from MSCs. We explore IL-6's mechanisms affecting neuronal function, survival, and immune modulation in the central nervous system. Additionally, we discuss the potential of MSC-derived IL-6 in neuroregeneration and neuroprotection. By elucidating IL-6's interplay with neurological pathologies, this review offers insights into novel therapeutic strategies targeting IL-6 signaling pathways for neurological disorders.

Citing Articles

Recent advances in mesenchymal stem cell therapy for multiple sclerosis: clinical applications and challenges.

Sheikhi K, Ghaderi S, Firouzi H, Rahimibarghani S, Shabani E, Afkhami H Front Cell Dev Biol. 2025; 13:1517369.

PMID: 39963155 PMC: 11830822. DOI: 10.3389/fcell.2025.1517369.

Effects of Repetitive Transcranial Magnetic Stimulation on Tumor Necrosis Factor Alpha in Neuropsychological Disorders: A Systematic Review and Meta-Analysis.

Asadizeidabadi A, Hosseini S, Pyatkov A Brain Behav. 2025; 15(2):e70329.

PMID: 39935210 PMC: 11814483. DOI: 10.1002/brb3.70329.

Genetic and peripheral biomarkers of comorbid posttraumatic stress disorder and traumatic brain injury: a systematic review.

Cowansage K, Nair R, Lara-Ruiz J, Berman D, Boyd C, Milligan T Front Neurol. 2025; 16:1500667.

PMID: 39931547 PMC: 11807831. DOI: 10.3389/fneur.2025.1500667.

Stem Cell Therapy for Diseases of Livestock Animals: An In-Depth Review.

Narasimha R, Shreya S, Jayabal V, Yadav V, Rath P, Mishra B Vet Sci. 2025; 12(1).

PMID: 39852942 PMC: 11768649. DOI: 10.3390/vetsci12010067.

Interleukin-6 Receptor Gene rs1800795 Polymorphism and Expression of Interleukin-6 in Gingival Tissue in Patients with Periodontitis.

Mazurek-Mochol M, Bonsmann T, Malinowski D, Serwin K, Czerewaty M, Safranow K Microorganisms. 2024; 12(10).

PMID: 39458264 PMC: 11509941. DOI: 10.3390/microorganisms12101954.

References

Narazaki M, Kishimoto T . Current status and prospects of IL-6-targeting therapy. Expert Rev Clin Pharmacol. 2022; 15(5):575-592. DOI: 10.1080/17512433.2022.2097905. View

Sterling J, Kam T, Guttha S, Park H, Baumann B, Mehrabani-Tabari A . Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein. Cell Rep. 2022; 38(7):110358. PMC: 8898592. DOI: 10.1016/j.celrep.2022.110358. View

Raper J, Bosinger S, Johnson Z, Tharp G, Moran S, Chan A . Increased irritability, anxiety, and immune reactivity in transgenic Huntington's disease monkeys. Brain Behav Immun. 2016; 58:181-190. PMC: 5067193. DOI: 10.1016/j.bbi.2016.07.004. View

Joe A, Yi L, Natarajan A, Le Grand F, So L, Wang J . Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol. 2010; 12(2):153-63. PMC: 4580288. DOI: 10.1038/ncb2015. View

Tackey E, Lipsky P, Illei G . Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus. 2004; 13(5):339-43. PMC: 2014821. DOI: 10.1191/0961203304lu1023oa. View

Hou G, Lv Z, Liu W, Xiong S, Zhang Q, Li C . An aquatic virus exploits the IL6-STAT3-HSP90 signaling axis to promote viral entry. PLoS Pathog. 2023; 19(4):e1011320. PMC: 10166480. DOI: 10.1371/journal.ppat.1011320. View

Li N, Hua J . Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017; 74(13):2345-2360. PMC: 11107583. DOI: 10.1007/s00018-017-2473-5. View

Pronto-Laborinho A, Pinto S, Gromicho M, Pereira M, Swash M, de Carvalho M . Interleukin-6 and amyotrophic lateral sclerosis. J Neurol Sci. 2019; 398:50-53. DOI: 10.1016/j.jns.2019.01.026. View

Dorronsoro A, Lang V, Ferrin I, Fernandez-Rueda J, Zabaleta L, Perez-Ruiz E . Intracellular role of IL-6 in mesenchymal stromal cell immunosuppression and proliferation. Sci Rep. 2020; 10(1):21853. PMC: 7736882. DOI: 10.1038/s41598-020-78864-4. View

10.

Huang Z, Wong L, Su Y, Huang X, Wang N, Chen H . Blood-brain barrier integrity in the pathogenesis of Alzheimer's disease. Front Neuroendocrinol. 2020; 59:100857. DOI: 10.1016/j.yfrne.2020.100857. View

11.

Lopez-Santalla M, Fernandez-Perez R, Garin M . Mesenchymal Stem/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications. Cells. 2020; 9(8). PMC: 7465092. DOI: 10.3390/cells9081852. View

12.

Brodacki B, Staszewski J, Toczylowska B, Kozlowska E, Drela N, Chalimoniuk M . Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett. 2008; 441(2):158-62. DOI: 10.1016/j.neulet.2008.06.040. View

13.

Toh W, Lai R, Hui J, Lim S . MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin Cell Dev Biol. 2016; 67:56-64. DOI: 10.1016/j.semcdb.2016.11.008. View

14.

Shan C, Zhang C, Zhang C . The Role of IL-6 in Neurodegenerative Disorders. Neurochem Res. 2024; 49(4):834-846. DOI: 10.1007/s11064-023-04085-6. View

15.

Nguyen H, Noss E, Mizoguchi F, Huppertz C, Wei K, Watts G . Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators. Immunity. 2017; 46(2):220-232. PMC: 5567864. DOI: 10.1016/j.immuni.2017.01.004. View

16.

Vilotic A, Nacka-Aleksic M, Pirkovic A, Bojic-Trbojevic Z, Dekanski D, Jovanovic Krivokuca M . IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies. Int J Mol Sci. 2022; 23(23). PMC: 9738067. DOI: 10.3390/ijms232314574. View

17.

Cartmell T, Poole S, Turnbull A, Rothwell N, Luheshi G . Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J Physiol. 2000; 526 Pt 3:653-61. PMC: 2270040. DOI: 10.1111/j.1469-7793.2000.00653.x. View

18.

Bakker A, Jaspers R . IL-6 and IGF-1 Signaling Within and Between Muscle and Bone: How Important is the mTOR Pathway for Bone Metabolism?. Curr Osteoporos Rep. 2015; 13(3):131-9. PMC: 4417129. DOI: 10.1007/s11914-015-0264-1. View

19.

Dzamko N . Cytokine activity in Parkinson's disease. Neuronal Signal. 2023; 7(4):NS20220063. PMC: 10695743. DOI: 10.1042/NS20220063. View

20.

Saadh M, Mikhailova M, Rasoolzadegan S, Falaki M, Akhavanfar R, Gonzales J . Therapeutic potential of mesenchymal stem/stromal cells (MSCs)-based cell therapy for inflammatory bowel diseases (IBD) therapy. Eur J Med Res. 2023; 28(1):47. PMC: 9881387. DOI: 10.1186/s40001-023-01008-7. View