Interleukin-4 receptor signaling modulates neuronal network activity

Abstract

Evidence is emerging that immune responses not only play a part in the central nervous system (CNS) in diseases but may also be relevant for healthy conditions. We discovered a major role for the interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4Rα) signaling pathway in synaptic processes, as indicated by transcriptome analysis in IL-4Rα–deficient mice and human neurons with/without IL-4 treatment. Moreover, IL-4Rα is expressed presynaptically, and locally available IL-4 regulates synaptic transmission. We found reduced synaptic vesicle pools, altered postsynaptic currents, and a higher excitatory drive in cortical networks of IL-4Rα–deficient neurons. Acute effects of IL-4 treatment on postsynaptic currents in wild-type neurons were mediated via PKCγ signaling release and led to increased inhibitory activity supporting the findings in IL-4Rα–deficient neurons. In fact, the deficiency of IL-4Rα resulted in increased network activity in vivo, accompanied by altered exploration and anxiety-related learning behavior; general learning and memory was unchanged. In conclusion, neuronal IL-4Rα and its presynaptic prevalence appear relevant for maintaining homeostasis of CNS synaptic function.

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

“…This work reveals a novel role for ILC2s and IL-13 signaling to interneurons to promote inhibitory synapses in early life and sociability in adulthood. Furthermore, we demonstrate a unique developmental role for IL-13 signaling to interneurons that may be distinct from other roles for IL-4 receptor in the adult brain, which are ILC2-independent (Derecki et al, 2010; Herz et al, 2021; Vogelaar et al, 2018; Hanuscheck et al, 2022; Brombacher et al, 2017, 2020; Li et al, 2023). While these and other studies have clearly demonstrated that lymphocyte-derived cytokines impact the brain, these cells are largely outside the blood brain barrier (BBB).…”

IL-4 shaping glutamatergic synapse like structures for more mature iPSC derived neuron phenotypes

“…In addition to glia and immune cell populations resident in the brain, IL-4RA protein is expressed in both excitatory and inhibitory neurons in cortex and hippocampus (Hanuscheck et al, 2022). Both brain regions are critically involved in cognitive performance and memory (Izquierdo et al, 2006; Jensen & Lisman, 2005).…”

“…Previous studies report impairment of learning induced by a global IL-4 depletion which is rescued by IL-4–expressing T cells suggesting an indirect pathway putatively involving IL-4Ra expressing astrocytes (Derecki et al, 2010). The functional consequences of depleting IL-4RA specifically in neurons affect inhibitory as well as excitatory neuron populations and lead to controversial outcome if synaptic vesicle pools are reduced, postsynaptic currents altered, but excitatory drive increased in cortical networks of IL-4RA–deficient neurons (Hanuscheck et al, 2022). Improved exploratory behavior and locomotion, anxiety levels and mitigated fear learning through inhibitory synapses are reported in mice with a neuronal depletion of IL-4RA (GABAergic (Herz et al, 2021).…”

“…In addition, IL-4 improves neuronal outgrowth and repair through a fast neuron-specific signaling pathway involving regulation of presynaptic vesicular glutamate transporter vGLUT1 in the central nervous system (cns) (Hanuscheck et al, 2020; Vogelaar et al, 2018). Although type 2 cytokines have been associated with pathological itch (Oetjen et al, 2017), the majority of findings suggest a homeostatic role of IL-4 and its receptors in neurogenesis, synaptic function, and neuronal regeneration after injury (Butovsky et al, 2006; Hanuscheck et al, 2022; Pan et al, 2022; Salvador, de Lima, & Kipnis, 2021). IL-4 secreting cells are recruited to the injury site within the cns or the injured nerve, and the secreted IL-4 promotes regeneration and repair (Pan et al, 2022; Walsh et al, 2015).…”

Chronic IL-1-induced DNA double-strand break response in hippocampal neurons drives cognitive deficits

“…Cytokines are known to play both beneficial and detrimental roles in the CNS 22–26 . While basal signaling by Interferon-γ 27 , Interleukin (IL)-17 28 , IL-4 29 , IL-1α 30 , IL-33 31 play important neuromodulatory roles underlying social behavior, short-term or fear memory encoding, respectively, IL-1β, IL6, IL-17, IL-33 32,33 , Tumor Necrosis Factor-α, and Interferon α and γ also mediate chronic pathological signaling, which in turn leads to neuronal dysfunction 22,34 . Chronically elevated levels of circulating IL-1, IL-6, TNF-α, or IFN-α lead to persistent alterations in neurotransmitters like glutamate, and impair neuronal growth factor function 25,35 .…”