The Communication Between the Immune and Nervous Systems: The Role of IL-1β in Synaptopathies

Abstract

In the last 15 years, groundbreaking genetic progress has underlined a convergence onto coherent synaptic pathways for most psychiatric and neurodevelopmental disorders, which are now collectively called "synaptopathies." However, the modest size of inheritance detected so far indicates a multifactorial etiology for these disorders, underlining the key contribution of environmental effects to them. Inflammation is known to influence the risk and/or severity of a variety of synaptopathies. In particular, pro-inflammatory cytokines, produced and released in the brain by activated astrocytes and microglia, may play a pivotal role in these pathologies. Although the link between immune system activation and defects in cognitive processes is nowadays clearly established, the knowledge of the molecular mechanisms by which inflammatory mediators specifically hit synaptic components implicated in synaptopathies is still in its infancy. This review summarizes recent evidence showing that the pro-inflammatory cytokine interleukin-1β (IL-1β) specifically targets synaptopathy molecular substrate, leading to memory defects and pathological processes. In particular, we describe three specific pathways through which IL-1β affects (1) synaptic maintenance/dendritic complexity, (2) spine morphology, and (3) the excitatory/inhibitory balance. We coin the term immune synaptopathies to identify this class of diseases.

Keywords: IL-1β; IL1RAPL1; KCC2; MeCP2; cytokines; inflammation; neurodevelopmental diseases; synaptopathies.

FIGURE 1

Cartoon depicting three possible pathways through which IL-1β might affect synaptic function and structure by acting on IL-R1 which is localized at synaptic site (Gardoni et al., 2011). Pathway 1: IL1RAPL1 mediates some of the effects of IL-1β in neurons, altering dendritic morphology. Pathway 2: IL-1β affects spine morphogenesis enhancing the expression of the transcription factor Mecp2, which in turn alters the expression of synaptic proteins via chromatin-remodeling mechanisms. Pathway3: IL-1β modulates the excitatory to inhibitory switch of GABA by reducing the expression of the chloride transporter KCC2, leading to E/I unbalance and higher susceptibility to seizures. Pathways 2 and 3 could be linked based on the REST/MeCP2 ability to bind KCC2 gene promoter and act as a repressor of the transporter transcription (see text for details).

FIGURE 2

Schematic representation summarizing the functional effects of the three regulatory pathways controlled by IL-1β. (A) IL-1β affects dendritic complexity through IL1RAPL1-dependent mechanisms. This pathway activates JNK and PTPδ intracellular proteins (Montani et al., 2017). (B) IL-1β regulates dendritic spine morphology by upregulating the transcription factor MeCP2 in an mTOR-dependent manner (Tomasoni et al., 2017). (C) IL-1β leads to an excitatory/inhibitory unbalance by delaying the developmentally regulated switch of GABA signaling. This pathway involves the interplay between the two transcription factors REST and MeCP2, which in turn regulates the transcriptional level of KCC2 (Corradini et al., 2017).