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Interleukin-31-mediated photoablation of pruritogenic epidermal neurons reduces itch-associated behaviours in mice

Abstract

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.

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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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.

Author information

L.N. and P.A.H. conceived the study. L.N. performed the experiments together with N.R., M.D., R.D., A.T. and L.C. M.M. performed gel analyses with IL-31SNAP and IL-31K138A–SNAP and synthesized BG–IR700. E.P. contributed to histological experiments. C.H.C contributed to the FACS experiments and data analysis. L.N. and P.A.H. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Correspondence to Linda Nocchi or Paul A. Heppenstall.

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Fig. 1: IL-31SNAP labelling and photoablation.
Fig. 2: Functional analysis of IL-31K138A–SNAP.
Fig. 3: IL-31K138A–SNAP-guided photoablation prevents and reverses atopic dermatitis-like symptoms.
Fig. 4: IL-31K138A–SNAP-guided photoablation reverses the indicators of FPLCA.
Fig. 5: Epidermal free nerve endings are the cellular target of IL-31K138A–SNAP-guided photoablation.