Interleukin 18 and the brain: neuronal functions, neuronal survival and psycho-neuro-immunology during stress

Abstract

Interleukin 18 (IL-18) is a pleiotropic cytokine that regulates peripheral innate and adaptive immune response and is also expressed in the brain. Here, we summarize the current knowledge on the biology of IL-18 in the brain and the efforts to determine its significance concerning neurological and psychiatric conditions. The picture that emerges is that of a heavily regulated molecule that can contribute to neuroinflammatory-mediated neuronal survival but can also serve as a neuromodulator that affects behaviour. We also summarize evidence showing how the brain can control the synthesis of peripheral IL-18 during stress by hormonal and neuronal signalling, regulating tissue-specific promoter usage. We discuss how this may represent one of the mechanisms by which the brain affects immune functions and what its implications are when considering IL-18 as a biomarker of psychiatric conditions.

Fig. 1. Expression of IL-18 in the brain.

Schematic representation of the sites and cells demonstrated to produce IL-18 in the CNS following treatment with LPS or during stress. This figure was created with Biorender at www.biorender.com.

Fig. 2. The “IL-18 system”.

Extracellular pro-IL-18 is activated after being cleaved by proteases (mainly caspase-1). Once matured, IL-18 can bind to IL-18BP, which acts as an endogenous inhibitor since the cytokine has a higher affinity for this protein than for IL-18R. IL-18 first binds to IL-18RαI with low affinity; subsequently, the IL-18Rβ chain is recruited, forming a high-affinity heterodimeric receptor complex. Following the formation of the canonical IL-18R complex, at least two signaling transduction pathways have been shown to be activated by IL-18. The Interleukin-1 receptor-associated kinase (IRAK)/Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) pathway leading to activation of the nuclear factor kappalight-chain-enhancer of activated B cells (NF-κB), and the mitogen-activated protein kinase (MAPK)/ Signal transducer and activator of transcription 3 (STAT3) to regulate gene transcription. Whether this signaling can contribute to modulate neuronal activity by regulating io channels remains to be determined (?). Truncated variants of the alpha (IL-18RαII) and beta (sIL-18Rβ) chains of the heterodimeric receptor could act as additional negative regulatory systems for IL-18 signaling, as the formation of complexes with these receptor isoforms does not induce signal activation. This figure was created with Biorender at www.biorender.com.

Fig. 3. Schematic representation of the mechanisms that regulate stress-dependent production of peripheral IL-18.

A IL-18 can be induced (1) during stress in the posterior pituitary gland and in the adrenocortical glands via corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) and (2) during infection or injection of lipopolysaccharides (LPS) in leukocytes. Stress can also activate the (3) parasympathetic nervous system, which was proposed to attenuate the induction of IL-18 during infection via acetylcholine (ACh). B The gene encoding for IL-18 has at least two distinct promoters that are used for tissue-specific for transcribing IL-18 during sterile neurogenic stimulation in the adrenal cortex (Promoter 1) or during infection in leukocytes (Promoter 2). See main text for details. This figure was created with Biorender at www.biorender.com.