Interleukin-31 and Pruritic Skin

Skin inflammation often evokes pruritus, which is the major subjective symptom in many inflammatory skin diseases such as atopic dermatitis and prurigo nodularis. Pruritus or itch is a specific sensation found only in the skin. Recent studies have stressed the pivotal role played by interleukin-31 (IL-31) in the sensation of pruritus. IL-31 is produced by various cells including T helper 2 cells, macrophages, dendritic cells and eosinophils. IL-31 signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor β. Recent clinical trials have shown that the anti-IL-31RA antibody nemolizumab can successfully decrease pruritus in patients with atopic dermatitis and prurigo nodularis. The IL-31 pathway and pruritic skin are highlighted in this review article.


Introduction
Pruritus or itch is a specific sensation of the skin leading to a scratching behavior mostly recognized in terrestrial mammals [1,2]. Acute pruritus is typically not a major problem. However, chronic pruritus that lasts more than 6 weeks is highly problematic because it markedly deteriorates quality of life, mental health and sleep quality in the afflicted individuals [1][2][3][4][5]. Chronic pruritus is the major symptom in many inflammatory skin diseases such as atopic dermatitis, prurigo nodularis, eczema, chronic urticaria and psoriasis [1][2][3][4]. Scratching clearly exacerbates the predisposing dermatitis, which may further enhance pruritus and result in an itch/scratch vicious cycle [6].
The production of IL-31 is upregulated by IL-4-mediated activation of signal transducer and activator of transcription 6 (STAT6) or by IL-33-mediated NF-κB activation [22], while it is downregulated by the activation of suppressor of cytokine signaling 3 (SOCS3) [23]. Staphylococcal enterotoxin B and staphylococcal α-toxin are potent inducers of IL-31 from peripheral blood mononuclear cells, probably via toll-like receptor (TLR)-4 activation [24][25][26]. Interestingly, transforming growth factor-β1 (TGF-β1) decreases IL-31 production in Th2 cells [22], but it enhances that in dendritic cells [18]. Endothelial PAS domain protein 1 (EPAS1), also called hypoxia-inducible factor-2α, is one of the direct targets of STAT6 and acts as a hub protein in IL-4-mediated transcription networks in human T cells [27]. The binding of Epas1 and another transcription factor, Sp1, to the promoter region of the Il31 gene is indispensable for IL-31 production by IL-4 [28].
As described in previous review articles [7,50,51], the sensation of pruritus in the skin is mediated by cutaneous sensory nerves of small diameter (C-fibers or thinly myelinated Aδ-fibers) originating from dorsal root ganglion (DRG) neuronal cells, and is transmitted to the spinal cord and hypothalamic tract, and ultimately to the brain. Recent studies have demonstrated various pruritogens, pruritogen-specific neurotransmitters and their receptors [7,50,51] (Table 1). BAM8-22, SLIGR and cathepsin S induce pruritus via Mas-related G-protein-coupled receptor C11 (MrgprC11) [9]. Most MrgprC11 + cutaneous sensory neurons are positive for substance P and calcitonin gene-related peptide (CGRP) in mice [9] ( Figure 2). The majority of Mas-related G-protein-coupled receptor C11 (MrgprC11)-positive murine sensory nerve fibers possess substance P and CGRP. MrgprC11 + sensory nerve fibers are positive for TRPV1 and TRPA1 which evokes action potential mainly via Ca 2+ . These MrgprC11 + sensory nerve fibers mostly coexpress IL-31 receptor (IL-31RA/OS-MRβ), which signals IL-31-induced pruritus to DRG neurons, the spinal cord, the hypothalamic tract and finally to the brain. The IL-31-induced pruritus is mediated by NKB and its receptor NK3R, and then by GRP and its receptor GRPR. Most MrgprC11 + nerve fibers also coexpress other pruritogenic receptors such as H1R for histamine, MrgprA3 for chloroquine, 5-HTR1F for serotonin and IL-4Rα/IL-13Rα1 for IL-4/IL-13. Pruritus by histamine and chloroquine is mediated by NPPB and its receptor NPRA, and then by GRP-GRPR signaling. Chronic pruritus is known to be associated with astrocytosis of the spinal cord. Many abbreviated molecules are listed in Table 1.
In addition to mediating the sensation of pruritus, IL-31 promotes nerve fiber elongation and the branching of murine small-diameter DRG neurons [48,57], which is abrogated in DRG neurons from Il31ra-deficient mice [48]. Moreover, the IL-31-induced nerve fiber elongation is independent of TRPV1 but dependent on STAT3 activation [48]. Interestingly, STAT3 also plays a pivotal role in the formation of reactive astrogliosis in the spinal cord, which causes chronic itch [58]. Targeting the STAT3 axis is thus a potential strategy for treating chronic pruritus (Figure 2).
The majority of Mas-related G-protein-coupled receptor C11 (MrgprC11)-positive murine sensory nerve fibers possess substance P and CGRP. MrgprC11 + sensory nerve fibers are positive for TRPV1 and TRPA1 which evokes action potential mainly via Ca 2+ . These MrgprC11 + sensory nerve fibers mostly coexpress IL-31 receptor (IL-31RA/OSMRβ), which signals IL-31-induced pruritus to DRG neurons, the spinal cord, the hypothalamic tract and finally to the brain. The IL-31-induced pruritus is mediated by NKB and its receptor NK3R, and then by GRP and its receptor GRPR. Most MrgprC11 + nerve fibers also coexpress other pruritogenic receptors such as H1R for histamine, MrgprA3 for chloroquine, 5-HTR1F for serotonin and IL-4Rα/IL-13Rα1 for IL-4/IL-13. Pruritus by histamine and chloroquine is mediated by NPPB and its receptor NPRA, and then by GRP-GRPR signaling. Chronic pruritus is known to be associated with astrocytosis of the spinal cord. Many abbreviated molecules are listed in Table 1.
In addition to mediating the sensation of pruritus, IL-31 promotes nerve fiber elongation and the branching of murine small-diameter DRG neurons [48,57], which is abrogated in DRG neurons from Il31ra-deficient mice [48]. Moreover, the IL-31-induced nerve fiber elongation is independent of TRPV1 but dependent on STAT3 activation [48]. Interestingly, STAT3 also plays a pivotal role in the formation of reactive astrogliosis in the spinal cord, which causes chronic itch [58]. Targeting the STAT3 axis is thus a potential strategy for treating chronic pruritus ( Figure 2).

IL-31 and Keratinocytes
In addition to its pruritogenic function, IL-31 is known to directly inhibit the differentiation of keratinocytes by downregulating the expression of barrier/differentiation-related proteins such as filaggrin, involucrin and cytokeratin 10, which results in the disruption of epidermal barrier function [38,59,60]. IL-31 also increases the expression of IL-1α, IL-20 and IL-24 in keratinocytes and these cytokines are partly responsible for IL-31-mediated downregulation of skin barrier formation [38,60]. In contrast, IL-31 increases the production of antimicrobial peptides such as S100A7 and defensin β4 [60]. Significant amounts of IL-31 are detected in human sweat [20]. Upon stimulation with IL-31, keratinocytes can produce CCL2 [20]. However, the pathophysiological role of IL-31 in keratinocyte biology is not fully understood.

IL-31 in Skin Diseases with Pruritus
As IL-31 is a potent pruritogenic cytokine, its levels in skin and serum have been examined in various pruritic skin diseases. Increased IL-31 expression was found in lesional and nonlesional skin of patients with atopic dermatitis [24,61,62]. In addition, IL-31-expressing T cells are increased in the lesional skin of atopic dermatitis [62]. Serum levels of IL-31 are well correlated with disease severity in atopic patients [63,64]. Serum levels of IL-31 are elevated in canine atopic dermatitis and are significantly correlated with the pruritus score of afflicted dogs [65].
Prurigo nodularis is associated with severe pruritus. In this condition, the intensity of pruritus is correlated with the numbers of dermal IL-31 + cells and dermal IL-31RA + cells [17]. Major cellular sources of dermal IL-31 are T cells and macrophages, while IL-31RA-expressing cells are mostly mast cells and macrophages [17].
The number of IL-31RA + or OSMRβ + cells is also correlated with pruritus intensity in patients with bullous pemphigoid [15]. Most of the dermal cells expressing IL-31 are eosinophils in bullous pemphigoid [15].
The majority of IL-31-expressing cells are CD68 + macrophages in stasis dermatitis [16]. The number of IL-31 + CD68 + cells was shown to be significantly increased in stasis dermatitis with severe pruritus compared with that without severe pruritus [16]. These CD68 + macrophages also coexpress CD163 and are classified as M2 macrophages [16].
The preferential expression of IL-31 in CD163 + M2 macrophages also occurs in scabies infection [14].
Serum levels of IL-31 are significantly elevated in patients with chronic pruritus of unknown origin compared with those in healthy controls [66]. In addition, serum IL-31 levels are significantly increased in patients with chronic urticaria or psoriasis; however, no significant correlation was found between pruritus intensity and IL-31 levels in these diseases [67].
In patients receiving hemodialysis, individuals with uremic pruritus have significantly increased serum levels of IL-31 compared with the levels in those without pruritus [68]. Oweis et al. measured serum levels of IL-31, IL-13 and IL-33 in hemodialysis patients and healthy controls [69]. The serum level of IL-31, but not those of IL-13 and IL-33, was found to be significantly elevated in hemodialysis patients compared with that in healthy controls. However, the serum level of IL-13, but not those of IL-31 and IL-33, was revealed to be significantly correlated with itch intensity [69]. Serum and cutaneous levels of IL-31 are also elevated in cutaneous T-cell lymphoma [19,[70][71][72][73] and are described as being correlated with itch intensity in some reports [19,73]. In addition, the serum level of IL-31 is also increased in patients with intrahepatic cholestasis of pregnancy and hepatitis B virus-related liver cirrhosis, which are often associated with pruritus [74,75]. These studies stress the definite or potential role of IL-31 in pruritus induced by diverse skin disorders.

Control of Pruritus by Targeting IL-31 Signaling
The efficacy of anti-IL-31 treatment against pruritus was first proven in atopic dermatitis (Table 2). Table 2. Biologics targeting IL-31.
Recently, nemolizumab has also been reported to attenuate pruritus and skin inflammation associated with prurigo nodularis compared with placebo [11]. In addition, the anti-OSMRβ antibody vixarelimab (KPL-716) is now under a clinical trial for the treatment of prurigo nodularis (ClinicalTrials.gov Identifier: NCT03816891) [81].

Conclusions
Pruritus is a specific sensation associated with skin inflammation, such as atopic dermatitis and prurigo nodularis. Pruritus is also associated with systemic disorders such as kidney and liver diseases. Since chronic pruritus markedly deteriorates the quality of life of afflicted individuals, its therapeutic control is important. Recent studies have elucidated a close relationship of pruritus with IL-31, which is produced by Th2 cells, macrophages, dendritic cells and eosinophils. In accordance with this, intervention in the binding of IL-31 to its specific receptor IL-31RA/OSMRβ by specific antibodies has been proven to inhibit the pruritus in atopic dermatitis and prurigo nodularis. Targeting the IL-31 signal may thus be a promising strategy for improving the pruritus associated with diverse skin diseases.