IL-31 structure and function
The first major role of IL-31 was described in an induced mouse model of atopic dermatitis (AD), where it was reported to cause cutaneous inflammation along with pruritus when IL-31 was genetically overexpressed.1 Ever since this observation, IL-31 and its respective receptor heterodimer IL-31 receptor-A (IL31RA)/Oncostatin M receptor β (OSMRβ) have been studied for their role in tissue homeostasis, inflammation, immune defence, neuroimmune circuits and pruritus.
IL-31 belongs to the family of IL-6-derived cytokines. Interleukin-6 family cytokines are commonly clustered based on their pro-inflammatory character and a shared signaling pathway engaging in gp130 receptor subunit activation. The IL-6 cytokine family is often referred to as the gp130/IL-6 family of cytokines. Family members are IL-6, IL-11, IL-21, IL-27, neuropoietin (NPN), ciliary inhibitory factor (CNTF), cardiotropin-1 (CT-1), leukemia inhibitory factor (LIF), oncostatin M (OSM) and IL-31. Apart from IL-31, IL-6 family cytokines signal through a heterodimeric receptor composed of two subunits of which one typically is gp130.2 IL-31 does not engage with gp130 itself, but rather interacts with a heterodimer complex that is composed of the gp130-like subunit IL31RA and OSMRβ.1 This receptor heterodimer is activated with similar affinities by oncostatin M (OSM) and IL-31. The OSMRβ subunit is widely expressed throughout the various cell types of the mammalian body, while IL31RA subunit expression is predominantly observed in epithelial and neuronal cell types. In humans, IL31RA forms either a long or a short isoform, with the short isoform resuming a non-signaling inhibitory function. In rodents, only the long isoform has been detected.3 Engagement of OSM or IL-31 with the IL31RA/OSMRβ heterodimer initiates activation of canonical JAK/STAT, AKT/PI3K and MAPK-JNK/p38 pathways (Figure 1). Of note, at least MAPK activity is not inducible by signaling through the IL31RA alone but needs both receptor subunits to cooperate.4Activation of IL-31 signaling pathways leads to the induction of various cellular processes including cell survival, proliferation and differentiation.
The physiological function of IL-31 is still not fully understood. Recently, a major role for IL-31 in humans has been described in various inflammatory disorders, including AD, inflammatory bowel disease (IBD), nasal polyposis (NP) and airway hyperreactivity (AHR).
IL-31 has been identified as a secretory product of TH2 cells and immature dendritic cells (iDC),5 and activates IL31RA/OSMRβ receptor expressing dorsal root ganglia (DRG) neurons and keratinocytes, among others,3,5–7 linking immune cells to epithelium and the neuronal network in the skin, and probably also gut and airways.6 Intradermal application of IL-31 indeed leads to sensations of itch, underlying the capacity of IL-31 to activate target neurons.8 Here, we summarize our current understanding about the pathophysiological role of the IL-31/IL31RA/OSMRβ axis in skin and mucosa, with an emphasis on neuro-immune communication and its translational importance for the treatment of inflammatory and neuroimmune diseases of skin, gut and airways in the future.