# Neurons differentially upregulate type 2 immune cytokines and interleukin-4 receptor subtypes during neuroinflammation

## TL;DR

Neurons in the brain and spinal cord show increased expression of IL-4 and its receptor during neuroinflammation, suggesting neurons may play a role in immune responses.

## Contribution

The study reveals differential expression of IL-4 receptor subtypes and cytokines in neurons during neuroinflammation, with distinct regional patterns in the CNS.

## Key findings

- Neurons in the forebrain mainly express IL-4R type II, while spinal cord neurons predominantly express IL-4R type I.
- Neuroinflammation increases IL-4Rα and its ligands in neurons, while receptor co-chains are downregulated.
- Both IL-4 and IL-13 are upregulated in neurons during neuroinflammation.

## Abstract

Although numerous studies demonstrate beneficial effects of exogenous interleukin-4 (IL-4) in different central nervous system (CNS) disease models, little is known about the expression of IL-4 and its receptor (IL-4R) system in neurons. We previously showed that the beneficial effects of exogenous IL-4 in neuroinflammation depend on functional neuronal IL-4Rα. Here, we demonstrate neuronal expression of IL-4Rα, the receptor co-chains IL-2Rγ (IL-4R type I) and IL-13Rα1 (IL-4R type II), as well as the type 2 immune cytokines IL-4 and IL-13 throughout the brain and spinal cord of healthy mice and of mice subjected to experimental autoimmune encephalomyelitis (EAE). Surprisingly, we observed differential expression of the receptor chains in different regions of the CNS, with forebrain neurons expressing mainly IL-4R type II and spinal cord neurons showing prominent IL-2Rγ signals (IL-4R type I), the latter mainly known in immune cells. Moreover, we found that the regulation of the system was mainly driven by the increase of IL-4Rα-expressing neurons at the peak of neuroinflammation, whereas the co-chains are downregulated. Additionally, we showed neuronal expression of IL-4 and IL-13 throughout the CNS and observed upregulation of these cytokines during neuroinflammation. Our data indicate that neurons upregulate both IL-4Rα and its ligands during neuroinflammation.

The online version contains supplementary material available at 10.1186/s40478-026-02229-7.