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.

A Novel Quinolyl‐Substituted Analogue of Resveratrol Inhibits LPS‐Induced Inflammatory Responses in Microglial Cells by Blocking the NF‐κB/MAPK Signaling Pathways

“…Neuroinflammation is a complex immune process that performs diverse functions and plays a homeostatic role in the brain. However, uncontrolled or prolonged neuroinflammation is potentially harmful . Microglia, the macrophages in the brain, are considered to have a critical function in the immune surveillance of the central nervous system .…”

“…However, uncontrolled or prolonged neuroinflammation is potentially harmful. [10][11][12] Microglia, the macrophages in the brain, are considered to have a critical function in the immune surveillance of the central nervous system. [13] Microglia can become activated and secrete a variety of pro-inflammatory mediators in response to stimulation.…”

Neuroimmune System as a Driving Force for Plasticity Following CNS Injury

“…Moreover, remodeling of cortical dendritic spines following systemic inflammation is suggested to be mediated by TNFα and contributes to deficits in learning and cognitive function (Garre et al, 2017 ). IL-1β is also among the most notable cytokines contributing to such synaptic plasticity via direct and indirect mechanisms of modulating the structure and function of dendritic spines (Li et al, 2003 ; Gilmore et al, 2004 ), number of synaptic sites (Mishra et al, 2012 ), and synapse stabilization (reviewed in more detail in Besedovsky and del Rey, 2011 ; Pozzi et al, 2018 ; Rizzo et al, 2018 ). Furthermore, numerous cytokines are suggested to influence long-term potentiation (LTP) of synaptic transmission between neurons via gliogenic paracrine signaling and may, therefore, contribute to the development of pain hypersensitivity and cognitive dysfunction (Besedovsky and del Rey, 2011 ; Kronschläger et al, 2016 ).…”

Continuous administration of the p38α inhibitor neflamapimod during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level

“…Brain-derived neurotrophic factor (BDNF) promotes neural plasticity and recovery after stroke [35] and the proinflammatory cytokine interleukin-1 beta (IL-1) is upregulated after ischemic stroke [36][37][38][39][40]. In subacute/chronic inflammatory conditions, IL-1 is known to be a key component of the inflammatory response in the brain that mediates neurodegenerative effects of inflammation on cognition and synaptic plasticity [41].…”