Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB

Yunjin Lee¹, Tomoe Ishikawa², Hyeseung Lee³, Byeongjun Lee², Changhyeon Ryu², Irene Davila Mejia², Minjin Kim¹, Guangqing Lu¹, Yujin Hong¹, Mengyang Feng², Hyeyoon Shin¹, Sylvain Meloche⁴, Richard M Locksley⁵, Ekaterina Koltsova⁶, Sergei I Grivennikov⁷, Myriam Heiman³, Gloria B Choi⁸, Jun R Huh⁹

Affiliations

¹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
² Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Institute for Research in Immunology and Cancer (IRIC), Montreal, QC, Canada.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
⁶ Departments of Medicine and Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Departments of Medicine and Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁸ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: gbchoi@mit.edu.
⁹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Human Biology Microbiome Quantum Research Center (Bio2Q), Keio University, Tokyo, Japan; Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA, USA. Electronic address: jun_huh@hms.harvard.edu.

PMID: 40199322
PMCID: PMC12063771 (available on 2026-04-17)
DOI: 10.1016/j.cell.2025.03.006

Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB

Yunjin Lee et al. Cell. 2025.

. 2025 Apr 17;188(8):2203-2217.e17.

doi: 10.1016/j.cell.2025.03.006. Epub 2025 Apr 7.

Authors

Affiliations

¹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
² Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Institute for Research in Immunology and Cancer (IRIC), Montreal, QC, Canada.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
⁶ Departments of Medicine and Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Departments of Medicine and Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁸ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: gbchoi@mit.edu.
⁹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Human Biology Microbiome Quantum Research Center (Bio2Q), Keio University, Tokyo, Japan; Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA, USA. Electronic address: jun_huh@hms.harvard.edu.

PMID: 40199322
PMCID: PMC12063771 (available on 2026-04-17)
DOI: 10.1016/j.cell.2025.03.006

Abstract

Cytokines interact with their receptor complexes to orchestrate diverse processes-from immune responses to behavioral modulation. Interleukin-17A (IL-17A) mediates protective immune responses by binding to IL-17 receptor A (IL-17RA) and IL-17RC subunits. IL-17A also modulates social interaction, yet the role of cytokine receptors in this process and their expression in the brain remains poorly characterized. Here, we mapped the brain-region-specific expression of all major IL-17R subunits and found that in addition to IL-17RA, IL-17RB-but not IL-17RC-plays a role in social behaviors through its expression in the cortex. We further showed that IL-17E, expressed in cortical neurons, enhances social interaction by acting on IL-17RA- and IL-17RB-expressing neurons. These findings highlight an IL-17 circuit within the cortex that modulates social behaviors. Thus, characterizing spatially restricted cytokine receptor expression can be leveraged to elucidate how cytokines function as critical messengers mediating neuroimmune interactions to shape animal behaviors.

Keywords: IL-17 receptor; IL-17A; IL-17E (IL-25); IL-17RB; autism; cytokine receptor; social interaction.

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Conflict of interest statement

Declaration of interests J.R.H. and G.B.C. consult for CJ CheilJedang, hy, and Interon Laboratories. J.R.H. is an advisor on the Samsung Bio Advisory Board.

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Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB

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Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB

Authors

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Abstract

Conflict of interest statement

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