The Cytokine TGF-β Induces Interleukin-31 Expression from Dermal Dendritic Cells to Activate Sensory Neurons and Stimulate Wound Itching

Abstract

Summary Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31 −/− mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-β1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1 f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo . Thus, cDC2s promote itching during skin would healing via a TGF-β-IL-31 axis with implications for treatment of wound itching.

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

“…Indeed, stimulation of airway epithelial cells with IL-31 induced an increased production of MCP1 and IL-6 cytokines known to play a role in the development of pulmonary fibrosis ( 46 ). Recent studies have revealed that the expression of IL-31 was dependent of TGF-β1 signaling in different cell types and disease conditions including fibrosis and skin wound healing ( 22 , 47 , 48 ). However, TGF- β1 independent pathways might also regulate the expression of IL-31 on CD4+ T cells.…”

Dendritic Cells Revisited

“…Similarly, CLEC-2 upregulated on activated cDCs during immune challenge binds to podoplanin on LN FRCs, inhibiting contractility signaling and permitting FRC stretching and LN expansion (215). A recent paper indicates that cDCs can also communicate with sensory neurons: IL-31 released by activated dermal cDC2s in response to TGF-β produced during cutaneous wound healing acts on itch sensory neurons to potentiate the itching response of wounded mice (177).…”

Targeted inhibition of EPAS1-driven IL-31 production by a small-molecule compound

“…Although CD4 1 T cells are main source of IL-31 in AD, [3][4][5][6] other cells such as dermal dendritic cells also produce IL-31 in different contexts. 20 Therefore, how IPHBA affects IL-31 production by other cells is an important issue that should be investigated in future studies.…”