Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch
Open accessAbstract
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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Itch mechanisms are complex, involving multiple mediators that activate peripheral sensory neurons, and they offer several pharmacological targets.
“The mechanisms that underlie itching sensation are complex, involving multiple mediators that initiate the activation of peripheral sensory neurons. They offer a number of potential targets for pharmacological intervention29,180–182.”
From Atopic dermatitis: an expanding therapeutic pipeline for a complex disease (2022) · cites this paper as [180]
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References 66 · Cited by 1,092
- Authors
- Oetjen, L. K., Mack, M. R., Feng, J., Whelan, T. M., Niu, H., Guo, C. J., Chen, S., Trier, A. M., Xu, A. Z., Tripathi, S. V., Luo, J., Gao, X., Yang, L., Hamilton, S. L., Wang, P. L., Brestoff, J. R., Council, M. L., Brasington, R., Schaffer, A., Brombacher, F., Hsieh, C.-S., Gereau, R. W., Miller, M. J., Chen, Z.-F., Hu, H., Davidson, S., Liu, Q., & Kim, B. S.
- Affiliations
- Washington University in St. Louis (US)
- University of Cincinnati (US)
- University of Cape Town (ZA)
- Corresponding author
- Kim, Brian S.
- ORCID
- Oetjen, Landon K.
- Mack, Madison R.
- Feng, Jing
- Niu, Haixia
- Guo, Changxiong J.
- Chen, Sisi
- Trier, Anna M.
- Xu, Amy Z.
- Luo, Jialie
- Yang, Lihua
- Hamilton, Samantha L.
- Brestoff, Jonathan R.
- Schaffer, András
- Brombacher, Frank
- Hsieh, Chyi-Song
- Gereau, Robert W.
- Miller, Mark J.
- Chen, Zhou-Feng
- Hu, Hongzhen
- Davidson, Steve
- Liu, Qin
- Kim, Brian S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 171
- Issue
- 1
- Pages
- 217-228.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5658016
- OpenAlex
- W2752706812
- Cited by
- 1,092
- References
- 66
- Citations by year
- 2026: 127 · 2025: 133 · 2024: 146 · 2023: 144 · 2022: 125 · 2021: 147 · 2020: 117 · 2019: 85 · 2018: 55 · 2017: 10 · 2012: 1
- FWCI
- 83.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- WUSM Institute of Clinical and Translational Sciences
- ICTS
- NIH National Center for Advancing Translational Sciences
- NCATS (UL1TR000448, P30CA91842)
- National Center for Research Resources
- NCRR
- NCRR Shared Instrumentation (1S10RR027552)
- NIDDK (P30DK052574, R01DK103901)
- NINDS (R01NS042595)
- NIAMS (R21AR068012, K08AR065577, R01AR070116)
- NIGMS (R01GM101218)
- American Skin Association
- Doris Duke Charitable Foundation
- NHLBI (T32HL007317)
- Howard Hughes Medical Institute
- HHMI
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- chronic pruritus, pruritus, sensory neurons, type 2 cytokines, IL-4 receptor alpha, JAK inhibitors, neuroimmune signaling, atopic dermatitis, asthma, scratching behavior
- MeSH terms
- Animals, Ganglia, Spinal, Humans, Mice, Inbred C57BL, Pruritus, Sensory Receptor Cells, Skin Diseases, Signal Transduction, Interleukin-4, Interleukin-13, Mice, Janus Kinase 1
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