THE IMPACT OF IL-1 IN NEUROLOGICAL FUNCTIONING

Letter to the Editor

G. D’Amario^*

Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy.

*Correspondence to:
Giulia D’Amario,
Department of Neuroscience,
Catholic University of the Sacred Heart,
00168 Rome, Italy.
e-mail: giuliadamario@gmail.com

Received: 02 January, 2025 Accepted: 28 February, 2025

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2025 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

KEYWORDS: IL-1, interleukin, cytokine, inflammation, neuroinflammation, CNS, neurological

INTRODUCTION

IL-1 is a regulator of both physiological and pathological processes, and its dysregulation can cause neuroinflammation and neurodegeneration. The interleukin-1 (IL-1) family primarily includes IL-1α, IL-1β and IL-1 receptor antagonist (IL-1Ra), an endogenous inhibitor. In general, IL-1 is involved in inflammatory reactions, infections, and neurological disorders (1,2). IL-1 is a pro-inflammatory cytokine that plays a key role in the immune response and has significant effects on the brain. It has multiple effects on the central nervous system (CNS) and can be inhibited by specific antagonists of the IL-1 receptor (3). IL-1 is primarily produced by activated macrophages, microglia, and astrocytes in the CNS and can exert various effects on brain physiology and pathology.

DISCUSSION

The cytokine IL-1 plays different roles in the brain, where it mediates inflammatory responses and modulates neuronal function. IL-1 is involved in slow-wave sleep, neuroendocrine responses, appetite suppression, fever, and neuroinflammation (4). This cytokine also affects memory and neuroplasticity and has been associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases (5).

In vivo studies in mice have shown that IL-1 can interact with GABA receptors to induce sleep and depression (6). IL-1 binds to the IL-1 receptor type 1 (IL-1R1) on the surface of target cells and interacts with the IL-1 receptor accessory protein (IL-1RAcP) to form a signaling complex. At the transductional level, IL-1 recruits myeloid differentiation primary response 88 (MyD88) as an adaptor protein. IL-1 activates kinases including IL-1 receptor-associated kinase (IRAK) and TNF receptor-associated factor 6 (TRF-6).

IL-1 stimulates the NF-κB and mitogen activated protein kinase (MAPK) signaling pathways and activates the inflammasome (7). The NLRP3 inflammasome is important for the processing of pro-IL-1β into its mature and active form via caspase-1. IL-1 is regulated by IL-1Ra which competitively inhibits the binding of IL-1 to IL-1R1 while the IL-1 receptor type 2 (IL-1R2) acts as a decoy receptor, controlling the effect of IL-1.

IL-1 is involved in brain pathophysiology, including neuroinflammation. It mediates infectious and neurodegenerative responses by recruiting immune cells to the site and amplifying the inflammatory reaction. It has been reported that IL-1 can increase the vascular permeability of the blood-brain barrier (BBB) to allow the passage of immune cells into brain tissue and contribute to neurodegeneration (8). Among the effects of IL-1 on the brain, it is important to highlight its action on the hypothalamus with the induction of fever by mediating effects such as increased body temperature with systemic inflammation, anorexia, and lethargy. At low levels, IL-1 helps maintain normal synaptic plasticity and regulates cognitive function, while its excessive increase causes neurodegeneration. In fact, by stimulating the production of amyloid-β and phosphorylation of tau, IL-1 participates in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. It activates microglia, causing damage and neuronal disorders (9).  IL-1 can influence neurogenesis in the hippocampus, altering the mood of the individual. Its inflammatory effect on the brain can cause depression, anxiety and other mental disorders. It has been seen that IL-1 also plays a role in the development of the embryo, interrupting normal brain maturation, which could be linked to diseases such as autism in which the cause is still unknown. Thus, it could be proposed that inhibiting IL-1 with specific cytokines could improve its pathological effects. IL-1 inhibition may be an important therapeutic strategy for neurodegenerative diseases and other brain pathologies.

CONCLUSIONS

IL-1 is a cytokine that, when elevated above physiological limits, is highly inflammatory. This cytokine is produced by macrophages and by microglia in the brain. IL-1 binds to IL-1R1, can interact with GABA receptors to induce sleep and depression, and is implicated in Alzheimer’s disease and Parkinson’s disease. Inhibiting IL-1 with IL-1 receptor antagonists or anti-inflammatory cytokines may be a valid and novel therapy for neurodegenerative diseases.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunological Reviews. 2017;281(1):8-27. doi:https://doi.org/10.1111/imr.12621
2. Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2012;493(7434):674-678. doi:https://doi.org/10.1038/nature11729
3. Hsieh CT, Lee YJ, Lee JW, et al. Interleukin-1 receptor antagonist ameliorates the pain hypersensitivity, spinal inflammation and oxidative stress induced by systemic lipopolysaccharide in neonatal rats. Neurochemistry International. 2020;135:104686-104686. doi:https://doi.org/10.1016/j.neuint.2020.104686
4. Huang TR, Jou SB, Chou YJ, Yi PL, Chen CJ, Chang FC. Interleukin-1 receptor (IL-1R) mediates epilepsy-induced sleep disruption. BMC Neuroscience. 2016;17(1). doi:https://doi.org/10.1186/s12868-016-0309-0
5. Dong X, Zhang L, Meng Q, Gao Q. Association Between Interleukin-1A, Interleukin-1B, and Bridging integrator 1 Polymorphisms and Alzheimer’s Disease: a standard and Cumulative Meta-analysis. Molecular neurobiology. 2016;54(1):736-747. doi:https://doi.org/10.1007/s12035-015-9683-3
6. Yan X, Jiang E, Weng HR. Activation of toll like receptor 4 attenuates GABA synthesis and postsynaptic GABA receptor activities in the spinal dorsal horn via releasing interleukin-1 beta. Journal of Neuroinflammation. 2015;12(1):222. doi:https://doi.org/10.1186/s12974-014-0222-3
7. Gao Y, Xu X, Feng J, et al. Effects of interleukin-1 receptor-associated kinase 1 RNA interference in dendritic cells on inflammatory cytokine release and T-cell proliferation. Molecular Medicine Reports. 2016;14(6):5685-5692. doi:https://doi.org/10.3892/mmr.2016.5946
8. Gloor SM, Weber A, Adachi N, Frei K. Interleukin-1 Modulates Protein Tyrosine Phosphatase Activity and Permeability of Brain Endothelial Cells. Biochemical and Biophysical Research Communications. 1997;239(3):804-809. doi:https://doi.org/10.1006/bbrc.1997.7557
9. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481-487. doi:https://doi.org/10.1038/nature21029