Role of Histamine on Itch Sensation Induced by Interleukin-31

Masahiro Seike, MD, Ph D

1 Department of Food and Nutrition Science, Sagami Women’s Junior College, 2-1-1 Bunkyo Minami-ku Sagamihara Kanagawa 252-0383 Japan.

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Masahiro Seike, Department of Food and Nutrition Science, Sagami Women’s Junior College, 2-1-1 Bunkyo Minami-ku Sagamihara Kanagawa 252-0383 Japan.
Email: seike_masahiro@isc.sagami-wu.ac.jp
Telephone: +81-42-749-4784

Received: July 19, 2021
Revised: August 31, 2021
Accepted: September 2, 2021
Published online: May 30, 2022


Chronic allergic dermatitis, including atopic dermatitis and chronic allergic contact dermatitis, is characterized by an itch sensation and eczematous lesions, along with T helper (Th) 2 cell and granulocyte infiltration. Th2 cells, mast cells and eosinophils secrete interleukin (IL)-31, inducing intense itching in allergic dermatitis. Regulatory T cells (Tregs) inhibit the infiltration of these cells. Histamine induces the development of eczematous lesions in patients with chronic allergic dermatitis. In these eczematous lesions, histamine induces cell infiltration and inhibits Treg infiltration via histamine H1 and H4 receptors. Therefore, histamine may aggravate the itch sensation during chronic allergic dermatitis by increasing IL-31 levels.

Key words: Allergic dermatitis; Itch sensation; IL-31; Histamine

© 2022 The Authors. Published by ACT Publishing Group Ltd. All rights reserved.

Seike M. Role of Histamine on Itch Sensation Induced by Interleukin-31. Journal of Dermatological Research 2022; 7(1): 225-231 Available from: URL: http://www.ghrnet.org/index.php/jdr/article/view/3187


Chronic allergic dermatitis, such as atopic dermatitis (AD) and chronic allergic contact dermatitis (CACD), is characterized by pruritus and eczematous lesions accompanied by T helper (Th) 2 cell infiltration. Interleukin (IL)-31 is primarily secreted by Th2 cells[1]. Granulocytes are an additional source of IL-31[2-5]. Patients with AD, chronic spontaneous urticaria, CACD, prurigo nodularis, primary cutaneous lymphoma or mastocytosis exhibit increased levels of IL-31 protein and elevated IL-31 mRNA in the skin[6]. IL-31 is regulated by exposure to allergens[7]. IL-31 signals are mediated via a heterodimeric receptor complex comprising IL-31 receptor A (IL-31RA) and oncostation M receptor (OSMR)[8-10]. The IL-31 receptor is expressed in macrophages, dendritic cells, basophils, cutaneous neurons and keratinocytes[11-17]. Furthermore, small-diameter neurons in the dorsal root ganglia (DRG) express IL-31RA[11]. IL-31 may act directly on peripheral nerves, causing pruritus associated with AD[18].


Notably, Th2 cells primarily secrete IL-31[1]. IL-31 expression is dependent on autocrine IL-4 expression. IL-31 can induce proinflammatory genes, such as CC chemokine ligand 2 (CCL2) and granulocyte colony-stimulating factor[19]. Signal transducer and activator of transcription 6 (STAT6) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) are central players mediating IL-31 expression induced by IL-4 and IL-33. In contract, transforming growth factor (TGF)-β1 attenuates IL-31 secretion by Th2 cells[20]. IL-31RA induces STAT signaling, with the presence of a functional JAK-binding box within IL-31RA considered an essential prerequisite for functional IL-31-mediated STAT3 signaling. Suppressor of cytokine signaling-3 (SOCS3) acts as a potent feedback inhibitor of IL-31-inducing signaling[21]. In human keratinocytes, IL-31RA levels are upregulated by interferon-γ and a toll-like receptor (TLR) 2/TLR1 agonists, but not by IL-4[15]. IL-31RA levels are low in human macrophages, whereas they are upregulated by staphylococcal enterotoxin B or staphylococcal α-toxin[15,16].

Although Th2 cells remain the primary source of IL-31, granulocytes are an additional IL-31 source[7, 13, 22, 23]. IL-31 is robustly expressed in the skin of patients with chronic spontaneous urticaria and is released from isolated basophils following anti-IgE, IL-31, or N-formylmethionyl-leucyl-phenylalanine stimulation[13]. IL-31RA and OSMR are expressed in human basophils.

Human β-defensins (hBDs) and cathelicidin LL-37 enhance IL-31 gene expression, as well as IL-31 protein production and release, in the human mast cell line LAD2 and peripheral blood-derived mast cell cultures. IL-31 expression is found to be elevated in psoriatic skin mast cells. hBD-2-4 and LL-37 activate the phosphorylation of mitogen-activated protein kinases, p38, ERK, and INK, which are required for IL-31 production and release[22]. Elevated serum levels of IL-31 can be observed in patients with myeloproliferative disorders, known to be characterized by pruritus. Additionally, mast cells of patients exhibit increased IL-31 secretion[24].

Human eosinophils can release IL-31, which is significantly more intense in eosinophils from patients with AD than in those from normal volunteers. IL-31 affects eosinophil functions by inducing chemotaxis, Ca2+ mobilization, CCL26 release, and reactive oxygen species generation[25]. IL-31RA, OSMR-β and IL-33 receptor component ST2 are expressed on the surface of eosinophils. A co-culture of eosinophils and fibroblasts was found to induce IL-6 and AD-related chemokines C-X-C motif chemokine ligand 1 (CXCL1), CXCL10, CCL2 and CCL5. The induction is further enhanced by IL-31 and IL-33 stimulation[4, 5].


Itch sensation emanates from the activity of itch-specific nerve fibers in the epidermis and can be attributed to mechano-insensitivity, low condition velocities, large innervation territories, and high transcutaneous electrical thresholds[26]. These nerve fibers extend to the stratum granulosum of the epidermis. It is well established that keratinocytes are predominant cells in the epidermis and release pruritogenic molecules (opioids, proteases, substance P, nerve growth factor [NGF], neurotrophin4, endocannabinoids) expressing various receptors involved in itch sensation, including, but not limited to, protease activated receptor (PAR) 2, vanilloid, transient receptor potential vanilloid (TRPV) ion channels, TrkA, TrkB, cannabinoid receptor 1, IL-31 receptor, and μ- and κ-opioid receptors. Keratinocytes act as initiators of the itch sensation and are responsible for communicating the itch signal to the cutaneous sensory nerves[27].

Cytokines play a crucial role in mediating mechanisms underlining itch. Thymic stromal lymphopoietin (TSLP) is a cytokine long implicated as a critical mediator of T-lymphocyte maturation and activation. TSLP directly promotes itch by activating cutaneous sensory neurons[28]. This TSLP-induced itch requires TRPA1, and the expression of keratinocyte-derived TSLP depends on the ORAI1/NFAT calcium signaling pathway[28]. Intradermal IL-2 injection induces itch sensation in patients with AD or healthy individuals[29]. On utilizing intravenous IL-2 for cancer therapy, severe pruritus is a known side effect of treatment[30-32]. In patients with AD, cyclosporine downregulated IL-2 synthesis and decreased pruritus [33]. Notably, IL-4 and IL-13 are necessary for the development, initiation, and maintenance of the Th2 subset of cells. IL-4 and IL-13 are associated with eosinophilic infiltration and the production of NGF and TrkA[34-36]. Pruritus was observed in transgenic mice overexpressing IL-4 and IL-13[37, 38]. IL-13 is a potent stimulator of pruritus in AD and appears to be involved in TRPV1 signaling[39]. Dupilmab, a monoclonal antibody targeting IL-4 and IL-13, demonstrated a 55.7% reduction in pruritus severity[40].

Gastrin-releasing peptide (GRP) is a neuropeptide involved in the itch sensation, as intradermal injections of GRP elicit scratching in mice[41]. GRP is released by neurons in the DRG[42-45] and activates dorsal spinal cord neurons expressing the GRP receptor, which, in turn, transmits the itch signal to higher-order neurons[46]. Severe pruritus in patients with AD positively corelated with serum GRP levels[47].

Acetylcholine (ACh) stimulates histaminergic and nonhistaminergic cutaneous sensory nerve C fibers[48, 49]. Intradermal ACh injection induced axonal reflexive flare response similar to that noted in histaminergic itch[50]. Patients with AD are more sensitive to intradermal ACh injections than to histamine[51]. Intradermal injections of ACh induced pain in healthy subjects, whereas itch sensation was observed in patients with AD[52].

Glucocorticoids stimulate the upregulation of cytokines that mediate Th2 responses, such as IL-4 and IL-13[53]. As IL-4 and IL-13 are implicated in the pathogenesis of itch, glucocorticoid secretion in response to psychological stress can be implicated as a mediator of itch[27].

Histamine is released from immune cells in response to tissue inflammation or allergen-induced stimulation[54-56]. Direct application of histamine to human skin induces itching and subsequent axonal reflexive vasodilation and flare[57]. There are four established histamine receptors (H1 receptor [H1R]-H4 receptor [H4R]) [50]. H1R and H4R have been identified as potential mediators of pruriception[56]. H1R is expressed in the DRG, and H1R inhibitors can completely suppress histamine-induced itch in human skin[56, 57]. Thus, H1R is an important mediator of histamine-induced itch reactions. However, a recent study showed that H4R inhibitors blocked itching in a murine allergic contact dermatitis (ACD) model[58]. Moreover, the concomitant blockage of H1R and H4R was more effective at reducing itch than either receptor alone[59].

Substance P (SP) is a neuropeptide involved in afferent neuronal signal transduction[60]. Activation of sensory neurons in the skin causes the release of SP[32, 61]. SP binds to neurokinin receptors on mast cells, keratinocytes, and cutaneous nerve ending, resulting in the release of additional itch mediators[48, 61]. In humans, intradermal injection of SP induced mast cell activation and histamine release, associated with a wheal and flare reaction[62-65]. Mast cells activated by SP reportedly release inflammatory mediators such as leukotriene B4, prostaglandin D2, and tumor necrosis factor-alpha[66-69]. Moreover, SP triggers the release of pruritogenic compounds from keratinocytes, endothelial cells, and immune cells[70, 71]. Notably, skin lesions in patients with AD and prurigo nodularis are characterized by increased SP-positive sensory neurons[72, 73]. Elevated serum SP levels have been detected in patients with AD and corelate with itch intensity[74].

Furthermore, histamine released from mast cells increases levels of NGF[75]. NGF is a neurotrophin that modulates the development of the peripheral nervous system, including cutaneous innervation, which induces pruritus. NGF is thought to precipitate neurohyperplasia in the skin lesion of patients with AD[76, 77]. Additionally, NGF upregulates SP and calcitonin gene-related peptide (CGRP)[78], both of which are related to neurogenic inflammation and hypersensitization of itch pruriceptors[67]. Eosinophils are the primary source of NGF, and the release of NGF can be associated with increased TRPV receptor 1 and intracellular calcium, which, in turn, release SP and CGRP via SNARE/synaptogoin/synaptobrevin mechanisms. Both SP and CGRP increase eosinophil chemotaxis, activation, and survival, thus, propagating a vicious itch cycle[27].


Notably, IL-31 transgenic mice, as well as those treated with IL-31, exhibited scratching behavior and AD-like skin lesions. Moreover, IL-31 induced an increase in cutaneous nerve fiber density in the skin lesions of these mice[79]. Murine DRG cultures treated with IL-31 demonstrated increased neuronal elongation. Therefore, IL-31 promotes sensitivity to pruritus in AD, and the IL-31 nerve axis may play a role in the skin hypersensitivity, a well-known characteristic of AD[79].

Cutaneous and intradermal injections of IL-31 evoke intense itching, with markedly increased concentrations detected in murine AD-like skin. Human and mouse DRG neurons express IL-31RA, mainly in neurons that express TRPV1. IL-31-induced itching behavior was shown to be significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1-deficient mice[11]. Pretreatment with an anti-IL-31 RA antibody inhibited scratching behavior induced by IL-31 injection. In contrast, a non-sedative antihistamine (terfenadine), immunosuppressants (dexamethasone and tacrolimus), or a μ-opioid receptor antagonist (naloxone) failed to significantly suppress scratching behavior. Anti-IL-31RA antibodies reduced ear swelling and dermatitis scores in a chronic pruritus-inducing AD-like murine model[80]. Transgenic mice overexpressing IL-31 were found to develop severe pruritus. IL-31R expression is increased in diseased tissues derived from an animal model of airway hypersensitivity[81]. Administration of an anti-mouse IL-31 antibody ameliorated scratching behavior in NC/Nga mice with AD-like skin lesion[82]. Il-31 transgenic mice or mice supplemented with an iso-osmotic pump containing IL-31 developed AD-like skin lesions with scratching[83], with the lesioned skin presenting hyperinnervation. Accordingly, IL-31 promotes nerve fiber elongation and branching of murine small-diameter DRG neurons, which are abrogated in DRG neurons from Il-31ra-deficient mice[83]. IL-31 binds to IL-31RA on the sensory nerve and evokes itch sensation via TRPV1 and TRPA1 ion channel activation. Additionally, IL-31 promotes the elongation and branching of IL-31RA+ sensory nerve fibers, which might self-aggravate itch sensation[84].

Cacine IL-31induces pruritic behaviours in dogs and can be detected in most dogs with naturally occurring AD[85]. IL-31 delivery elicited a scratching response immediately after IL-31 administration, persisting for at least 3 h in cynomolgus monkeys. Treatment with IL-31 monoclonal antibody inhibited the IL-31-mediated scratching response[86]. In cynomolgus monkeys, a single subcutaneous injection of nemolizumab, an anti-human IL-31RA monoclonal antibody, suppressed IL-31-induced scratching for approximately 2 months [87]. Furthermore, nemolizumab was efficacious and well-tolerated for up to 64 weeks in patients with moderate-to-severe AD inadequately controlled by topical therapy[88]. Nemolizumab rapidly and sustainably improved cutaneous signs of inflammation and pruritus in patients with AD, with the maximal efficacy observed at 30mg[89]. The use of subcutaneous nemolizumab, in addition to topical agents for AD, resulted in a greater reduction in pruritus than with the use of placebo plus topical agents. The incidence of injection-related reactions was 8% with nemolizumab and 3% with placebo[89]. Nemolizumab reduced pruritus and skin lesion severity in patients with prurigo nodularis. However, nemolizumab has been associated with gastrointestinal symptoms (abdominal pain and diarrhea) and musculoskeletal symptoms[89].


Histamine-deficient histidine decarboxylase (HDC, -/-) mice were used to investigate the role of histamine in the extent of CACD induced by repeated application of contact sensitizing agent. CACD was induced following the daily application of diphenylcyclopropenone (DCP). Histological examination of the skin revealed that mice displayed mast cell, eosinophil, and CD4+ T-cell infiltration. The magnitude of cell infiltration was more significant in HDC (+/+) mice than HDC (-/-) ones[90, 91]. Histamine mediates chemotaxis of mast cells and eosinophils via H1R or H4R in allergic tissues[91, 92]. Therefore, histamine plays a vital role in the development of eczematous lesions in patients with chronic allergic dermatitis. As human mast cells and eosinophils secrete IL-31, histamine may increase IL-31 levels and induce itch sensation in CACD via H1R and H4R in these cells. IL-4 levels were increased in HDC (+/+) mice when compared with that in HDC (-/-) mice; this increased IL-4 was ameliorated by H1R and H4R antagonist[90-92]. Moreover, as IL-4 induces the release of IL-31 from Th2 cells, histamine could increase IL-31 levels and induce itch sensation by increasing IL-4 levels. Moreover, these effects were induced by H1R and H4R.

Regulatory T cells (Tregs) are a subset of T cells known to regulate effector T cells, leading to immune tolerance to reduce allergic reactions, and play a role in maintaining immunological self-tolerance by actively suppressing self-reactive lymphocytes[93]. Tregs suppress effector T cells and ameliorate ACD[94]. TGF-β is one of the central regulators of Treg recruitment in allergic lesions[95]. As the level of TGF-β1 and number of Tregs in eczematous lesions is higher in HDC (-/-) mice than in HDC (+/+) mice, histamine suppresses Tregs mediated by TGF-β1 in skin lesions[96]. This suppression was found to be improved by H1R or H4R antagonist[96]. Furthermore, TGF-β1 attenuates IL-31 secretion by Th2 cells; accordingly, histamine may increase IL-31 levels and itch sensation by decreasing TGF-β1. Moreover, these effects were induced via H1R and H4R. Experimentally, scratching behavior was observed in HDC (+/+) mice but not in HDC (-/-) mice after DCP application[97]. Furthermore, scratching behavior was ameliorated in mice treated with H1R and H4R antagonist[98]. The roles of histamine in IL-31 and itch are summarized in Figure 1.

Figure 1 Flowchart of the article selection.


Chronic allergic dermatitis can be characterized by pruritus and eczematous lesions, accompanied by Th2 cell and granulocyte infiltration. These inflammatory cells secrete IL-31, which induces an itch sensation. Histamine promotes cell infiltration and inhibits Treg infiltration in allergic dermatitis via H1R and H4R. Finally, histamine may aggravate itch sensation in allergic dermatitis by increasing IL-31 levels.


I would like to thank Editage (www.editage.com) for English language editing.


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