Beyond an inflammatory mediator: Interleukin-1 in neurophysiology

Abstract

New findings: What is the topic of this review? This review focuses on the physiological role of the cytokine interleukin-1β in the CNS. What advances does it highlight? Traditionally, interleukin-1β is known as a key mediator of inflammation and immunity. This review highlights the more recent findings describing how interleukin-1β signalling is required to maintain homeostasis in the CNS.

Abstract: Since its discovery in the early 1940s, the interleukin-1 (IL-1) cytokine family has been associated primarily with acute and chronic inflammation. The family member IL-1β is produced by different leucocytes, endothelial cells and epithelial cells. This cytokine has been characterized as a key modulator of inflammation and innate immunity because it induces the transcription of several downstream inflammatory genes. More recently, several groups have demonstrated that IL-1β production is also required to maintain homeostasis in several organ systems. This review focuses on providing an overview of the more recently characterized role of IL-1β in the physiology of the CNS. So far, IL-1β signalling has been implicated in neuronal survival, neurite growth, synaptic pruning, synaptic transmission, neuroplasticity and neuroendocrine functions.

Keywords: central nervous system; cytokine; inflammation; interleukin-1β; neurophysiology.

FIGURE 1

Interleukin‐1β processing. Interleukin‐1β transcription is induced by PAMPs or DAMPs through activation of the NF‐κB signalling pathway (signal 1). The protein is produced as an inactive peptide (pro‐IL‐1β) that requires processing. A second stimulatory signal, such as ATP or ROS, induces assembly and activation of the inflammasome in the cytosol. Upon inflammasome activation, the protease pro‐caspase 1 is cleaved into caspase 1, which, in turn, cleaves pro‐IL‐1β into mature IL‐1β. Active IL‐1β can be released through pyroptosis or the release of exosomes and/or microvesicles. Created with BioRender. Abbreviations: ASC, adaptor molecule apoptosis‐associated speck‐like protein containing a CARD; ATP, adenosine trifosfate; DAMPs, damage‐associated molecular patterns; IκB, inhibitor of κB; IL‐1β, interleukin‐1β; NF‐κB, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; PAMPs, pathogen‐associated molecular patterns; ROS, reactive oxygen species.

FIGURE 2

Interleukin‐1β‐induced inflammatory genes. Interleukin‐1β binding to IL‐1R1 triggers the activation of the NF‐κB and MAPK signalling pathways, both of which induce the transcription of several inflammatory genes, such as interleukin 8 (IL‐8), interleukin 6 (IL‐6), chemokine (C‐C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF‐α), nitric oxide (NO) and different metalloproteinases (MMPs). Created with BioRender. Abbreviations: AP‐1, activator protein 1; ERK, extracellular signal‐regulated kinase; IκB, inhibitor of κB; IκBα, IκB kinase alpha; IκBβ, IkB kinase beta; IkBγ, IκB kinase gamma; IL‐1β, interleukin‐1β; IL‐1R1, interleukin‐1 receptor 1; IL‐1R2, interleukin‐1 receptor 2; JNK, c‐Jun N‐terminal kinase; NF‐κB, nuclear factor kappa B.

FIGURE 3

Interleukin‐1β as a key player in the CNS. Inflammatory and physiological effects of IL‐1β expression and signalling in the brain. Created with BioRender. Abbreviations: IL‐1β, interleukin‐1β.