Itch—a major symptom of many chronic skin diseases—can exacerbate inflammation by provoking scratching and subsequent skin damage. Here, we show that activation, via near infrared illumination, of a phototoxic agent that selectively targets itch-sensing cells can reduce itch-associated behaviours in mice. We generated a SNAP-tagged interleukin-31 (IL-31) ligand derivative (IL-31K138A–SNAP) that selectively binds receptors on itch-associated cells, without evoking IL-31-receptor signalling or scratching, and conjugated it to the photosensitizer IRDye 700DX phthalocyanine. Subcutaneous injection of IL-31K138A–SNAP–IR700 in mice followed by near infrared illumination resulted in the long-term reversal of the scratching behaviour evoked by the pruritogenic IL-31, an effect that was associated with the selective retraction of itch-sensing neurons in the skin. We also show that a topical preparation of IL-31K138A–SNAP–IR700 reversed the behavioural and dermatological indicators of disease in mouse models of atopic dermatitis and of the genetic skin disease familial primary localized cutaneous amyloidosis. Targeted photoablation may enable itch control for the treatment of inflammatory skin diseases.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $8.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ikoma, A., Steinhoff, M., Stander, S., Yosipovitch, G. & Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 7, 535–547 (2006).
Davidson, S. & Giesler, G. J. The multiple pathways for itch and their interactions with pain. Trends Neurosci. 33, 550–558 (2010).
Wahlgren, C. F. Itch and atopic dermatitis: an overview. J. Dermatol. 26, 770–779 (1999).
Elmariah, S. B. & Lerner, E. A. Topical therapies for pruritus. Semin. Cutan. Med. Surg. 30, 118–126 (2011).
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).
Rossbach, K. et al. Histamine H1, H3 and H4 receptors are involved in pruritus. Neuroscience 190, 89–102 (2011).
Liu, Q. et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353–1365 (2009).
Reich, A. & Szepietowski, J. C. Mediators of pruritus in psoriasis. Mediat. Inflamm. 2007, 64727 (2007).
Takano, N., Arai, I., Hashimoto, Y. & Kurachi, M. Evaluation of antipruritic effects of several agents on scratching behavior by NC/Nga mice. Eur. J. Pharmacol. 495, 159–165 (2004).
Steinhoff, M. et al. Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J. Invest. Dermatol. 126, 1705–1718 (2006).
Dillon, S. R. et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat. Immunol. 5, 752–760 (2004).
Grimstad, O. et al. Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis. Exp. Dermatol. 18, 35–43 (2009).
Bando, T., Morikawa, Y., Komori, T. & Senba, E. Complete overlap of interleukin-31 receptor A and oncostatin M receptor beta in the adult dorsal root ganglia with distinct developmental expression patterns. Neuroscience 142, 1263–1271 (2006).
Diveu, C. et al. Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling. Eur. Cytokine Netw. 15, 291–302 (2004).
Sonkoly, E. et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J. Allergy Clin. Immunol. 117, 411–417 (2006).
Miyagaki, T. et al. Increased CCL18 expression in patients with cutaneous T-cell lymphoma: association with disease severity and prognosis. J. Eur. Acad. Dermatol. Venereol. 27, e60–e67 (2013).
Raap, U. et al. Increased levels of serum IL-31 in chronic spontaneous urticaria. Exp. Dermatol. 19, 464–466 (2010).
Ohmatsu, H. et al. Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm. Venereol. 92, 282–283 (2012).
Takaoka, A. et al. Expression of IL-31 gene transcripts in NC/Nga mice with atopic dermatitis. Eur. J. Pharmacol. 516, 180–181 (2005).
Li, M. et al. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc. Natl Acad. Sci. USA 103, 11736–11741 (2006).
Raap, U. et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J. Allergy Clin. Immunol. 122, 421–423 (2008).
Singer, E. M. et al. IL-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus. J. Invest. Dermatol. 133, 2783–2785 (2013).
Schulz, F. et al. A common haplotype of the IL-31 gene influencing gene expression is associated with nonatopic eczema. J. Allergy Clin. Immunol. 120, 1097–1102 (2007).
Tanaka, A. et al. New insight into mechanisms of pruritus from molecular studies on familial primary localized cutaneous amyloidosis. Br. J. Dermatol. 161, 1217–1224 (2009).
Lee, D. D. et al. Genome-wide scan identifies a susceptibility locus for familial primary cutaneous amyloidosis on chromosome 5p13.1-q11.2. Br. J. Dermatol. 155, 1201–1208 (2006).
Arita, K. et al. Oncostatin M receptor-β mutations underlie familial primary localized cutaneous amyloidosis. Am. J. Hum. Genet. 82, 73–80 (2008).
Lin, M. W. et al. Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis. Eur. J. Hum. Genet. 18, 26–32 (2010).
Wang, W. H. et al. A new c.1845A→T of oncostatin M receptor-β mutation and slightly enhanced oncostatin M receptor-β expression in a Chinese family with primary localized cutaneous amyloidosis. Eur. J. Dermatol. 22, 29–33 (2012).
Zhang, Q., Putheti, P., Zhou, Q., Liu, Q. & Gao, W. Structures and biological functions of IL-31 and IL-31 receptors. Cytokine Growth Factor Rev. 19, 347–356 (2008).
Greaves, M. W. & Khalifa, N. Itch: more than skin deep. Int. Arch. Allergy Immunol. 135, 166–172 (2004).
Ruzicka, T. et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N. Engl. J. Med. 376, 826–835 (2017).
Nemoto, O. et al. The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study. Br. J. Dermatol. 174, 296–304 (2016).
Amoury, M. et al. Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand. Oncotarget 7, 54925–54936 (2016).
Le Saux, S. et al. Molecular dissection of human interleukin-31-mediated signal transduction through site-directed mutagenesis. J. Biol. Chem. 285, 3470–3477 (2010).
Dreuw, A. et al. Characterization of the signaling capacities of the novel gp130-like cytokine receptor. J. Biol. Chem. 279, 36112–36120 (2004).
Himes, R., Lee, S., McMenigall, K. & Russell-Jones, G. J. Reduction in inflammation in the footpad of carrageenan treated mice following the topical administration of anti-TNF molecules formulated in a micro-emulsion. J. Control Release 145, 210–213 (2010).
Tanaka, A. et al. The molecular skin pathology of familial primary localized cutaneous amyloidosis. Exp. Dermatol. 19, 416–423 (2010).
Neis, M. M. et al. Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J. Allergy Clin. Immunol. 118, 930–937 (2006).
Horejs-Hoeck, J. et al. Dendritic cells activated by IFN-ɣ/STAT1 express IL-31 receptor and release proinflammatory mediators upon IL-31 treatment. J. Immunol. 188, 5319–5326 (2012).
Heise, R. et al. IL-31 receptor alpha expression in epidermal keratinocytes is modulated by cell differentiation and interferon gamma. J. Invest. Dermatol. 129, 240–243 (2009).
Cornelissen, C., Luscher-Firzlaff, J., Baron, J. M. & Luscher, B. Signaling by IL-31 and functional consequences. Eur. J. Cell Biol. 91, 552–566 (2012).
Oetjen, L. K. et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 171, 217–228 (2017).
Mollanazar, N. K., Smith, P. K. & Yosipovitch, G. Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin. Rev. Allergy Immunol. 51, 263–292 (2016).
Osinka, K., Dumycz, K., Kwiek, B. & Feleszko, W. Novel therapeutic approaches to atopic dermatitis. Arch. Immunol. Ther. Exp. 66, 171–181 (2017).
Dolgin, E. First eczema biologic debuts but price could restrict use. Nat. Biotechnol. 35, 391–392 (2017).
Beck, L. A. et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N. Engl. J. Med. 371, 130–139 (2014).
Thaci, D. et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 387, 40–52 (2016).
Furue, M., Yamamura, K., Kido-Nakahara, M., Nakahara, T. & Fukui, Y. Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis. Allergy 73, 29–36 (2017).
Mitsunaga, M. et al. Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat. Med. 17, 1685–1691 (2011).
Cedeno-Laurent, F. et al. Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities. Clin. Immunol. 158, 1–7 (2015).
Gonzales, A. J. et al. Oclacitinib (APOQUEL) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. J. Vet. Pharmacol. Ther. 37, 317–324 (2014).
Yang, G. et al. Genetic targeting of chemical indicators in vivo. Nat. Methods 12, 137–139 (2015).
Han, L. et al. A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci. 16, 174–182 (2013).
Stantcheva, K. K. et al. A subpopulation of itch-sensing neurons marked by Ret and somatostatin expression. EMBO Rep. 17, 585–600 (2016).
Cevikbas, F. et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J. Allergy Clin. Immunol. 133, 448–460 (2014).
Usoskin, D. et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat. Neurosci. 18, 145–153 (2015).
Wilson, S. R. et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155, 285–295 (2013).
Rivard, J. & Lim, H. W. Ultraviolet phototherapy for pruritus. Dermatol. Ther. 18, 344–354 (2005).
Tarng, D. C., Cho, Y. L., Liu, H. N. & Huang, T. P. Hemodialysis-related pruritus: a double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream. Nephron 72, 617–622 (1996).
Wallengren, J. & Klinker, M. Successful treatment of notalgia paresthetica with topical capsaicin: vehicle-controlled, double-blind, crossover study. J. Am. Acad. Dermatol. 32, 287–289 (1995).
Stander, S., Luger, T. & Metze, D. Treatment of prurigo nodularis with topical capsaicin. J. Am. Acad. Dermatol. 44, 471–478 (2001).
Anand, P. & Bley, K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br. J. Anaesth. 107, 490–502 (2011).
Wallengren, J. & Sundler, F. Phototherapy reduces the number of epidermal and CGRP-positive dermal nerve fibres. Acta Derm. Venereol. 84, 111–115 (2004).
Hong, J., Buddenkotte, J., Berger, T. G. & Steinhoff, M. Management of itch in atopic dermatitis. Semin. Cutan. Med. Surg. 30, 71–86 (2011).
Dhandapani, R. et al. Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons. Nat. Commun. 9, 1640 (2018).
Directive n. 86/609 / EEC on the protection of animals used for experimental and other scientific purposes (Gazzetta Ufficiale della Repubblica Italiana, 1992); http://www.gazzettaufficiale.it/eli/id/1992/02/18/092G0157/sg
Lichti, U., Anders, J. & Yuspa, S. H. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat. Protoc. 3, 799–810 (2008).
McArthur, J. C., Stocks, E. A., Hauer, P., Cornblath, D. R. & Griffin, J. W. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch. Neurol. 55, 1513–1520 (1998).
Helft, J. & Merad, M. Isolation of cutaneous dendritic cells. Methods Mol. Biol. 595, 231–233 (2010).
Stoitzner, P., Romani, N., McLellan, A. D., Tripp, C. H. & Ebner, S. Isolation of skin dendritic cells from mouse and man. Methods Mol. Biol. 595, 235–248 (2010).
Bonin, R. P., Bories, C. & De Koninck, Y. A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments. Mol. Pain 10, 26 (2014).
Aida, T. et al. Cloning-free CRISPR/Cas system facilitates functional cassette knock-in in mice. Genome. Biol. 16, 87 (2015).
Di, T. T. et al. Astilbin inhibits Th17 cell differentiation and ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice via Jak3/Stat3 signaling pathway. Int. Immunopharmacol. 32, 32–38 (2016).
We thank P. Moreira of EMBL Transgenic Services, V. Paribeni and M. Gaetani for technical support of our work. We also acknowledge the assistance of the Protein Expression and Purification Core Facility for the generation of IL-31SNAP, IL-31K138A–SNAP and Cas9. This work was funded by EMBL and Fondazione Telethon.