To determine the relevance of interleukin-4 receptor (IL-4R) in brain homeostasis.

The cytokine interleukin (IL)-4 is long known to regulate inflammation. However, novel data on neuronal IL-4R expression in the CNS indicates additional roles of this pathway.

We utilized excitatory neuron-specific IL-4R-deficient mice and RNAseq on specific brain areas with and without stimulation, as well as a battery of behavioural tasks and electrophysiological analyses.

We discovered a role reversal of this immune cytokine: antigen-independent induction of neuroprotective IL-4 producing T cells via a MyD88-mediated mechanism in optic nerve and spinal cord injury (Walsh et al., J Clin Invest 2015) and direct neuronal IL-4 receptor signaling via the IRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair (Vogelaar et al., Sci Transl Med 2018). Further, we have now identified a specific role of the IL-4/IL-4R pathway for steady-state function and behaviour.

Given a specific neuronal expression pattern of IL-4R throughout the CNS and protective as well as regenerative effects of IL-4, this system beneficially impacts brain homeostasis.