Interleukin-31: The ‘itchy’ cytokine in inflammation and therapy

Abstract

Interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), rhinitis and airway hyperreactivity. In AD, IL-31 has been identified as one of the main ‘drivers’ of its cardinal symptom pruritus. Here, we aim to summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2-produced cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, and stimulating itch and neuronal outgrowth through activation of the heterodimer receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor β. IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well as various innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31 downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo nodularis. For example, whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.

Molecular and cellular mechanisms of itch and pain in atopic dermatitis and implications for novel therapeutics

“…T cell-derived pruritogenic IL-31 is upregulated in AD, and DRGs express high levels of the IL-31 receptor, which signals through extracellular signal-regulated kinase to induce itch. 16,19,32 Other cell types that express IL-31 include keratinocytes, eosinophils, basophils, mast cells, DCs and monocytes. 16,33 IL-31 induces the expression of neurokinin B, which is required for IL-31-mediated itch in DRG neurons.…”

“…128 Other injectable systemic therapies are currently in clinical trials for moderate-to-severe AD targeting IL-13 alone or IL-31. 16,36 Baricitinib, which is approved in the European Union for moderate-to-severe AD, is an orally available JAK1/2 inhibitor. 12 A phase 3 trial showed that at week 16, the proportion of patients with moderate-to-severe AD who achieved a 75% improvement in the EASI score from baseline (EASI-75) and a validated Investigator's Global Assessment for Atopic Dermatitis response (vIGA-AD) was significantly higher in the baricitinib 2-mg group than the placebo group.…”

“…15 Recruitment of T cells to AD lesions, production of IL-31 and subsequent activation of sensory neurons may drive and exacerbate itch. 16 Sensory neurons that express transient receptor potential vanilloid (TRPV) 1-4 17,18 and IL-31 receptor also express TRPV1 and TRPA1 ion channels, thus linking T cell-mediated and sensory nerve-mediated itch. 19 Neurons activated by cytokines, in turn, release neurotransmitters and neuropeptides that affect innate and adaptive immune cells.…”

“…16,19,32 Other cell types that express IL-31 include keratinocytes, eosinophils, basophils, mast cells, DCs and monocytes. 16,33 IL-31 induces the expression of neurokinin B, which is required for IL-31-mediated itch in DRG neurons. 34 IL-31 downregulates filaggrin expression.…”

Crosstalk between keratinocytes and immune cells in inflammatory skin diseases

“…IL-25 produced by keratinocytes also has a dual role in both inducing the Th2 response and inhibiting FLG synthesis in keratinocytes [82]. Moreover, both IL-33 and IL-4 can induce Th2 cells or mast cells to release IL-31 [83,84], and then IL-31 promotes pruritus and scratching behavior in AD [85]. Scratching the skin, in turns, further induces the expression and/or release of IL-33 and IL-25 from keratinocytes [81,86,87].…”