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STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch

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.

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Figure 1: Reactive astrogliosis occurs in the spinal dorsal horn in models of chronic itch.
Figure 2: Skin lesions maintain reactive astrocytes through TRPV1+ C-fibers.
Figure 3: Astrocytic STAT3 activation in the SDH is necessary for chronic itch and for spinal itch sensitization.
Figure 4: LCN2 is an astrocytic STAT3-dependent upregulated factor crucial for chronic itch.

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References

  1. Ikoma, A., Steinhoff, M., Ständer, S., Yosipovitch, G. & Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 7, 535–547 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Yosipovitch, G. & Bernhard, J.D. Clinical practice. Chronic pruritus. N. Engl. J. Med. 368, 1625–1634 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Dhand, A. & Aminoff, M.J. The neurology of itch. Brain 137, 313–322 (2014).

    Article  PubMed  Google Scholar 

  4. Sun, Y.-G. & Chen, Z.-F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448, 700–703 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Sun, Y.-G. et al. Cellular basis of itch sensation. Science 325, 1531–1534 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Mishra, S.K. & Hoon, M. The cells and circuitry for itch responses in mice. Science 340, 968–971 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. LaMotte, R.H., Dong, X. & Ringkamp, M. Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15, 19–31 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ikoma, A. Updated neurophysiology of itch. Biol. Pharm. Bull. 36, 1235–1240 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Miller, G. Grasping for clues to the biology of itch. Science 318, 188–189 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Halassa, M.M. & Haydon, P. Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu. Rev. Physiol. 72, 335–355 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Eroglu, C. & Barres, B. Regulation of synaptic connectivity by glia. Nature 468, 223–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Matsuda, H. et al. Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice. Int. Immunol. 9, 461–466 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sofroniew, M.V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  PubMed  Google Scholar 

  20. Lee, H. & Caterina, M.J. TRPV channels as thermosensory receptors in epithelial cells. Pflugers Arch. 451, 160–167 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bi, F. et al. Reactive astrocytes secrete lcn2 to promote neuron death. Proc. Natl. Acad. Sci. USA 110, 4069–4074 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zamanian, J.L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ikoma, A. et al. Neuronal sensitization for histamine-induced itch in lesional skin of patients with atopic dermatitis. Arch. Dermatol. 139, 1455–1458 (2003).

    PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. Suto, H. et al. NC/Nga mice: a mouse model for atopic dermatitis. Int. Arch. Allergy Immunol. 120 (suppl. 1), 70–75 (1999).

    Article  PubMed  Google Scholar 

  31. Leung, D.Y. Atopic dermatitis: immunobiology and treatment with immune modulators. Clin. Exp. Immunol. 107 (suppl. 1), 25–30 (1997).

    CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. Shimada, S.G. & LaMotte, R. Behavioral differentiation between itch and pain in mouse. Pain 139, 681–687 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Hashimoto, Y. et al. Scratching of their skin by NC/Nga mice leads to development of dermatitis. Life Sci. 76, 783–794 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Quackenbush, J. Microarray data normalization and transformation. Nat. Genet. 32 (suppl.), 496–501 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  PubMed  Google Scholar 

  38. 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).

    Article  PubMed  Google Scholar 

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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.

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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.

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Correspondence to Makoto Tsuda.

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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

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