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We previously showed that the beneficial effects of exogenous IL-4 in neuroinflammation depend on functional neuronal IL-4R\u03b1. Here, we demonstrate neuronal expression of IL-4R\u03b1, the receptor co-chains IL-2R\u03b3 (IL-4R type I) and IL-13R\u03b11 (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-2R\u03b3 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-4R\u03b1-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-4R\u03b1 and its ligands during neuroinflammation.<\/jats:p>","DOI":"10.1186\/s40478-026-02229-7","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T18:54:25Z","timestamp":1770922465000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neurons differentially upregulate type 2 immune cytokines and interleukin-4 receptor subtypes during neuroinflammation"],"prefix":"10.1186","volume":"14","author":[{"given":"Micaela","family":"Domingues","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"G\u00e4rtner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Hanuscheck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Schmaul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frauke","family":"Zipp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9683-7336","authenticated-orcid":false,"given":"Christina Francisca","family":"Vogelaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"2229_CR1","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.3389\/fimmu.2019.02507","volume":"10","author":"C Egholm","year":"2019","unstructured":"Egholm C, Heeb LEM, Impellizzieri D, Boyman O (2019) The regulatory effects of Interleukin-4 receptor signaling on neutrophils in type 2 immune responses. 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