Abstract
Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis1,2,3. Recent studies have revealed neuronal pathways selective for itch4,5,6,7,8, but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP)4, and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Ikoma, A., Steinhoff, M., Ständer, S., Yosipovitch, G. & Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 7, 535–547 (2006).
Yosipovitch, G. & Bernhard, J.D. Clinical practice. Chronic pruritus. N. Engl. J. Med. 368, 1625–1634 (2013).
Dhand, A. & Aminoff, M.J. The neurology of itch. Brain 137, 313–322 (2014).
Sun, Y.-G. & Chen, Z.-F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448, 700–703 (2007).
Sun, Y.-G. et al. Cellular basis of itch sensation. Science 325, 1531–1534 (2009).
Mishra, S.K. & Hoon, M. The cells and circuitry for itch responses in mice. Science 340, 968–971 (2013).
Bautista, D.M., Wilson, S.R. & Hoon, M.A. Why we scratch an itch: the molecules, cells and circuits of itch. Nat. Neurosci. 17, 175–182 (2014).
LaMotte, R.H., Dong, X. & Ringkamp, M. Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15, 19–31 (2014).
Ikoma, A. Updated neurophysiology of itch. Biol. Pharm. Bull. 36, 1235–1240 (2013).
Miller, G. Grasping for clues to the biology of itch. Science 318, 188–189 (2007).
Halassa, M.M. & Haydon, P. Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu. Rev. Physiol. 72, 335–355 (2010).
Eroglu, C. & Barres, B. Regulation of synaptic connectivity by glia. Nature 468, 223–231 (2010).
Matsuda, H. et al. Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice. Int. Immunol. 9, 461–466 (1997).
Shibata, T. et al. Glutamate transporter GLAST is expressed in the radial glia-astrocyte lineage of developing mouse spinal cord. J. Neurosci. 17, 9212–9219 (1997).
Sofroniew, M.V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).
Seike, M., Ikeda, M., Kodama, H., Terui, T. & Ohtsu, H. Inhibition of scratching behaviour caused by contact dermatitis in histidine decarboxylase gene knockout mice. Exp. Dermatol. 14, 169–175 (2005).
van der Steen, P.H., van Baar, H., Perret, C. & Happle, R. Treatment of alopecia areata with diphenylcyclopropenone. J. Am. Acad. Dermatol. 24, 253–257 (1991).
Takano, N., Sakurai, T. & Kurachi, M. Effects of anti-nerve growth factor antibody on symptoms in the NC/Nga mouse, an atopic dermatitis model. J. Pharmacol. Sci. 99, 277–286 (2005).
Sándor, K., Helyes, Z., Elekes, K. & Szolcsányi, J. Involvement of capsaicin-sensitive afferents and the transient receptor potential vanilloid 1 receptor in xylene-induced nocifensive behaviour and inflammation in the mouse. Neurosci. Lett. 451, 204–207 (2009).
Lee, H. & Caterina, M.J. TRPV channels as thermosensory receptors in epithelial cells. Pflugers Arch. 451, 160–167 (2005).
Cavanaugh, D.J. et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl. Acad. Sci. USA 106, 9075–9080 (2009).
Herrmann, J.E. et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J. Neurosci. 28, 7231–7243 (2008).
Bi, F. et al. Reactive astrocytes secrete lcn2 to promote neuron death. Proc. Natl. Acad. Sci. USA 110, 4069–4074 (2013).
Zamanian, J.L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).
Berard, J.L. et al. Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis. Glia 60, 1145–1159 (2012).
Mucha, M. et al. Lipocalin-2 controls neuronal excitability and anxiety by regulating dendritic spine formation and maturation. Proc. Natl. Acad. Sci. USA 108, 18436–18441 (2011).
Ikoma, A. et al. Neuronal sensitization for histamine-induced itch in lesional skin of patients with atopic dermatitis. Arch. Dermatol. 139, 1455–1458 (2003).
Takeda, K. et al. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161, 4652–4660 (1998).
Takano, N., Arai, I. & Kurachi, M. Analysis of the spontaneous scratching behavior by NC/Nga mice: a possible approach to evaluate antipruritics for subjects with atopic dermatitis. Eur. J. Pharmacol. 471, 223–228 (2003).
Suto, H. et al. NC/Nga mice: a mouse model for atopic dermatitis. Int. Arch. Allergy Immunol. 120 (suppl. 1), 70–75 (1999).
Leung, D.Y. Atopic dermatitis: immunobiology and treatment with immune modulators. Clin. Exp. Immunol. 107 (suppl. 1), 25–30 (1997).
Yasukawa, S. et al. An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells. Nat. Commun. 5, 3755 (2014).
Shimada, S.G. & LaMotte, R. Behavioral differentiation between itch and pain in mouse. Pain 139, 681–687 (2008).
Shimada, S.G., Shimada, K. & Collins, J. Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2. Eur. J. Pharmacol. 530, 281–283 (2006).
Hashimoto, Y. et al. Scratching of their skin by NC/Nga mice leads to development of dermatitis. Life Sci. 76, 783–794 (2004).
Quackenbush, J. Microarray data normalization and transformation. Nat. Genet. 32 (suppl.), 496–501 (2002).
Yamamoto, M. et al. A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC/Nga mice. Allergol. Int. 56, 139–148 (2007).
Yamamoto, M. et al. Contribution of itch-associated scratch behavior to the development of skin lesions in Dermatophagoides farinae-induced dermatitis model in NC/Nga mice. Arch. Dermatol. Res. 301, 739–746 (2009).
Acknowledgements
This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) through the 'Funding Program for Next Generation World-Leading Researchers (NEXT Program)' initiated by the Council for Science and Technology Policy (CSTP) (M.T.), from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.T. and K.I.), from Kyushu University (Progress 100) (M.T.), and from the Japan Science and Technology Agency (JST) through the Core Research for Evolutional Science and Technology (CREST) program (K.I.). We appreciate the technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University. We thank S. Akira (Osaka University) and H. Okano (Keio University) for providing critical materials (Lcn2−/− and Stat3flox/flox mice). We thank S. Takeuchi, H. Esaki and Y. Eguchi for providing critical advice on behavioral measurements and performing histological experiments. M.S-H. is a research fellow of the JSPS.
Author information
Authors and Affiliations
Contributions
M.S.-H. designed and performed most of the experiments, analyzed the data and wrote the manuscript. K.K., H.T., Y.K., C.Y. and A.H. assisted with some experiments. H.T.-S. provided shRNAmir plasmid and advice on plasmid construction. T.N. performed histological experiments of the skin and analyzed the data. J.H. provided advice on some experiments. S.A. and H.O. provided critical materials (Lcn2−/− and Stat3flox/flox mice) and advice on data interpretation. M.F. provided critical advice on behavioral measurement of chronic itch, skin histology and data interpretation. K.I. supervised the project and edited the manuscript. M.T. conceived the study, supervised the overall project, designed experiments, and wrote the manuscript. All of the authors read and discussed the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–11 & Supplementary Discussion (PDF 13084 kb)
Rights and permissions
About this article
Cite this article
Shiratori-Hayashi, M., Koga, K., Tozaki-Saitoh, H. et al. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat Med 21, 927–931 (2015). https://doi.org/10.1038/nm.3912
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.3912
This article is cited by
-
Human umbilical cord mesenchymal stem cell treatment alleviates symptoms in an atopic dermatitis-like mouse model
Stem Cell Research & Therapy (2023)
-
An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in Mice
Neuroscience Bulletin (2023)
-
Neuronal pentraxin 2 is required for facilitating excitatory synaptic inputs onto spinal neurons involved in pruriceptive transmission in a model of chronic itch
Nature Communications (2022)
-
Sympathetic Nerve Mediated Spinal Glia Activation Underlies Itch in a Cutaneous T-Cell Lymphoma Model
Neuroscience Bulletin (2022)
-
Manifestation of lipopolysaccharide-induced tolerance in neuro-glial primary cultures of the rat afferent somatosensory system
Inflammation Research (2021)