1. Please check and comment entries here.
Table of Contents

    Topic review

    Immune-Derived Mediators and Sensory Nerves for Itch Sensation

    Subjects: Allergy
    View times: 7
    Submitted by:


    Although histamine is a well-known itch mediator, histamine H1-receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch.

    1. Introduction

    Itch (or pruritus) is an unpleasant sensation inducing the desire to scratch [1], as well as being a major and distressing symptom of many skin and systemic diseases. Chronic itch represents a significant clinical problem resulting from renal [2], liver [3], and bowel diseases [4], as well as several serious skin diseases, such as atopic dermatitis (AD). Histamine is one of the best-evaluated itch mediators. If an itch is caused by histamine, antihistamines (histamine H1-receptor blockers) can be used to control it. However, recent studies have suggested that histamine-independent pathways are involved in chronic itch, making antihistamines ineffective in the treatment of these patients [5][6][7]. Thus, the mechanisms of itch development and enhancement other than through histamine remain to be determined. Analyses of the interactions between immune cells and sensory neurons have shown that cytokines produced by immune cells during inflammation enhance itch, and that they act directly on sensory nerve fibers to induce and/or sensitize itch sensation.

    2. Subtype of Sensory Neurons

    Generally, itch sensation is generated by the binding of itch-inducing substances (pruritogens) to their cognate receptors (pruriceptors) on peripheral sensory afferents, especially unmyelinated C-fibers [8]. Single-cell RNA-seq has classified the sensory neuron system into five neurofilament (NF)-containing clusters, two peptidergic (PEP) nociceptor clusters, a tyrosine hydroxylase (TH)-containing cluster and three non-peptidergic (NP) nociceptor clusters [9]. The NF clusters were shown to express neurofilament heavy chain (Nefh) and parvalbumin (Pvalb), molecules previously associated with myelinated dorsal root ganglion (DRG) neurons. The PEP clusters were found to express substance P (SP, also known as Tac1), TRKA (Ntrk1) and calcitonin gene-related peptide (CGRP, also known as Calca), molecules previously associated with peptidergic nociceptors. The TH cluster showed distinct expression of tyrosine hydroxylase (Th), which is also expressed in a distinct subclass of unmyelinated neurons. Finally, the NP clusters were found to express Mas-related G protein coupled receptor D (Mrgprd) and P2rx3, molecules previously associated with nonpeptidergic nociceptors. Notably, NP clusters express receptor genes for itch mediators.
    NP1 expresses the β-alanine receptor Mrgprd [10] and the lysophosphatidic acid receptors Lpar3 and Lpar5. Chloroquine (CQ) receptor (Mrgpra3) and bovine adrenal medulla (BAM) 8–22 receptor (Mrgprx1:human, Mrgprc11:mice) [11] are expressed on NP2; whereas the interleukin (IL)-31 receptor Il31ra, the oncostatin M receptor (OSM), the leukotriene (LT) C4 receptor Cysltr2 [12] and the serotonin receptors Htr1f and Htr2a are expressed on NP3. Histamine receptor (H1R) was detected on NP2 and NP3 [9] (Figure 1). In addition, NP1, NP2, and NP3 were found to be more enriched in neurons that express Il4ra and Il13ra1 than in other types of neurons such as NF and PEP [13].
    Figure 1. NP clusters of itch-related sensory nerves and itch-related receptors expressed on them. NP1 neurons are positive for IL-4Rα, IL-13 Rα and MrgprD (left). NP2 neurons are positive for IL-4Rα, IL-13 Rα, MrgprA3, MrgprC11 and H1R (middle). NP3 neurons are positive for IL-4Rα, IL-13 Rα, IL-31R, 5-HT2R, H1R and CysLTR2 (right).

    3. Itch Mediators and Modulators from Immune Cells

    Table 1 and Table 2 summarize the immune cell-derived itch mediators and modulators, and the therapeutic agents that target them. This section describes the itch mediators and modulators produced by immune cells. As detailed above, the primary sensory nerves associated with itch have been classified into at least three subtypes, each of which has its own response profile. Based on the subtypes of nerve cells, the itch mediators and modulators derived from immune cells are also summarized (Figure 2).
    Table 1. Immune cell-derived itch mediators and therapeutic methods.
    Category Pruritogens Receptors Therapeutic Methods Reference
    Amines Histamine H1R/H4R Anti-histamine/Anti-inflammatory, immuno-modulatory topical and systemic therapy (Cyclosporine A, Pimecrolimus, Tacrolimus and Corticosteroids) [6][14]
    Serotonin 5-HT2 receptor Sertraline [15]
    Proteases Tryptase PAR-2 Anti-histamine/Cyclosporine A/Pimecrolimus/Tacrolimus/Corticosteroids [6]
    Chymase PAR-2 ONO-WH-236/Anti-histamine/Cyclosporine A/Pimecrolimus/Tacrolimus/Corticosteroids [6][16]
    Cathepsin S PAR-2/PAR-4 LHVS/Anti-histamine/Cyclosporine A/Pimecrolimus/Tacrolimus/Corticosteroids [6][17]
    Peptides Substance P NK-1R Serlopitant/Gabapentin/Pregabalin/Capsaicin [6][18]
    Endothelin-1 ETA Bosentan [19]
    cytokines IL-2 IL-2R Cyclosporine A/Delgocitinib/Baricitinib/Abrocitinib [14][20][21][22][23]
    IL-4 IL-4Rα/γC Dupilumab/Delgocitinib/Baricitinib/Abrocitinib [14][24][25][26][23]
    IL-13 IL-4Rα/IL-13Rα1 Dupilumab/Tralokinumab/Lebrikizumab [14][24][25]
    IL-17 IL-17RA/IL-17RC Brodalumab [27]
    IL-23 IL-12Rβ1/IL-23R Delgocitinib/Baricitinib [14][28][29][23]
    IL-31 IL-31RA/OSMR Nemolizumab/Delgocitinib/Baricitinib/Abrocitinib [14][30][31][32][33][23][34]
    IL-33 ST2/IL-1RAcP Etokimab/Delgocitinib/Baricitinib [14][35][23]
    TSLP TSLPR Tezepelumab/Delgocitinib/Baricitinib/Abrocitinib [14][36][37][23][38]
    Lipid mediators PAF PAFR PAF antagonist [39][40]
    LTB4 BLT1/BLT2 CMHVA [41][42]
    LTC4 CysLTR1/CysLTR2 CysLTR2 antagonist [43]
    Table 2. Itch modulators from immune cells.
    Ligands Receptors Source Modulation
    SLIGRL-NH2 PAR-2 mast cells, basophils Enhances CQ and BAM8-22 induced itch
    IL-4 IL-4Rα/γC
    Th2, Tfh, ILC2, mast cells, basophils, eosinophils Enhanced neuronal responsiveness to histamine, CQ, TSLP and IL-31
    IL-13 IL-13Rα1/IL-13Rα2 Th2, ILC2, mast cells, basophils, eosinophils May enhance neuronal responsiveness to histamine, CQ, TSLP and IL-31, as well as IL-4
    IL-23 IL-12Rβ1/IL-23R DCs, macrophages Reduced histamine-induced itch
    IL-33 ST2/IL-1RAcP DCs, macrophages, mast cells Enhanced CQ evoked calcium responses

    3.1. Amines

    3.1.1. Histamine

    Histamine, the most well-known pruritogen, is produced by mast cells, basophils and keratinocytes [44][45][46][47][48][49][50][51]. Histamine evokes itch via histamine H1 and H4 receptors [49][52]. Histamine H1 receptor (H1R) is a G protein-coupled receptor (GPCR) [50][53][54][55], a class of receptors globally expressed in various tissues, including sensory nerves [47][51]. Histamine H4 receptor (H4R) is also a GPCR [50][54][55] and is mainly expressed in immunocompetent cells, including mast cells, eosinophils, neutrophils, monocytes, dendritic cells (DCs) and T cells; as well as in intestinal epithelia, spleen, lung, synovial tissue, the central nervous system (CNS), sensory neurons, and cancer cells [51][54][56]. H1R and H4R on histaminergic nerves bind histamine and then activate transient receptor potential vanilloid (TRPV) 1 [47][57]. The H4R antagonist, ZPL-3893787, improved AD symptoms including itch [14].
    A H3R inverse agonist was found to induce strong itch in mice. This H3R inverse agonist induced pruritus but could be completely blocked by combined treatment with an H1R and an H4R antagonist, whereas the H2R antagonist failed to inhibit the scratch response. The decreased threshold in response to H3R antagonism is thought to activate H1R and H4R on sensory neurons, leading to the excitation of histamine-sensitive afferents and eliciting a sensation of itch [58].

    3.1.2. Serotonin

    Serotonin (5-hydroxytryptamine; 5-HT), which is produced by mast cells, basophils and platelets [45][59][60][61][62], evokes scratching in rodents via the 5-HT2 receptor, which is TRPV4-dependent [63][64][65][66]. The 5-HT2 receptor is expressed in immunocompetent cells, including macrophages, DCs, Langerhans cells, CD3+ T cells, melanocytes, vascular smooth muscle cells, endothelial cells, central and peripheral neurons including primary sensory neurons (DRG/trigeminal ganglion cells) [60][67][68][69]. Activation of the 5-HT2 receptor, which belongs to the GPCR super-family and is coupled to the Gq/11 protein, leads to increases in inositol trisphosphate (IP3) and diacylglycerol (DG) levels, generating an antinociceptive effect [67][69]. Sertraline, a selective serotonin reuptake inhibitor, has been found to be effective in treating serotonin-targeted itch [15]. In addition, existing drugs, such as the selective 5-HT2 receptor antagonist sarpogrelate, may have expanded future clinical application in the treatment of itch.

    3.2. Proteases

    3.2.1. Tryptase

    Tryptase, a serine protease with trypsin-like specificity, consists of seven distinct isoforms, α, βI, βII, βIII, δ, ε and γ, encoded by a set of protease genes clustered together on chromosome 16p13.3 [70][71][72][73]. The tryptase best characterized to date is β-tryptase, and the term “tryptase” is often used as a synonym for this molecule [73]. Tryptase is expressed in mast cells and basophils [73][74][75][76][77]. Intradermal injection of tryptase elicits scratching in mice [78]. Proteases, including tryptase, activate protease-activated receptors (PARs) by cleaving a part of their extracellular domain. PARs are GRCRs, characterized by a unique mechanism of self-activation following specific proteolytic cleavage of their extracellular domains. To date, four PARs have been identified, PAR-1, PAR-2, PAR-3, and PAR-4, which are encoded by the F2RF2RL1F2RL2, and F2RL3 genes, respectively [79][80]. PAR-2 is activated by trypsin-like serine proteases and is widely distributed throughout the mammalian body. In the skin, PAR-2 is expressed by almost all cell types, especially by keratinocytes. In addition, endothelial cells, fibroblasts, sensory neurons, and inflammatory cells such as mast cells, T lymphocytes, eosinophils, neutrophils, monocytes, macrophages, and DCs have been reported to express functional PAR-2 [80]. Tethered ligands, such as the PAR-2 agonist SLIGRL-NH2, have been shown to elicit scratching in mice, but not rats [81]. Activated PAR-2 coactivates TRPV1 channels stimulating the release of the neuropeptides SP and CGRP from nerve terminals [82][83]. In addition, SLIGRL-NH2 enhances CQ- and BAM8-22-induced itch and acts as a modulator [84].

    3.2.2. Chymase

    Chymase is a chymotrypsin-like serine endopeptidase stored in mast cell secretory granules [48]. Human chymase, encoded by the CMA1 gene located on chromosome 14q11.2, co-localizes with clusters formed by cathepsin G, granzyme B and granzyme C/H [74][85][86]. In rats, the chymase-encoding gene is located on chromosome 15p12/13, and in mice on chromosome 14C1/2 [86][87][88][89][90]. Chymase also activates PAR-2 [16][91]. The chymase specific inhibitor Y-40613 was found to suppress scratching behavior in a mouse model of pruritus [92]. In the eyes, chymase also induced scratching behavior, which was suppressed by the selective chymase inhibitor ONO-WH-236 [91].

    3.2.3. Cathepsin S

    Cathepsin S is a cysteine protease produced by DCs, macrophages, basophils and keratinocytes [49][93][94]. Cathepsin S activates PAR-2, PAR-4 and MrgprC11 to produce itch [95][96][17]. Intradermal injection of the selective PAR-4 agonist AYPGKF-NH2 (AYP) elicited scratching behavior in mice [84][97], which was prevented by the selective PAR-4 antagonist (pepducin P4pal-10) [97]. AYP-induced itch was reduced by gastrin-releasing peptide (GRP), NK-1, TRPV1 and a TRPA1 antagonist. These results indicated that PAR-4-activated itch is induced via TRPV1/TRPA1 in mice [97]. Moreover, touch-evoked scratching (alloknesis) was observed following intradermal injection of AYP, but not PAR-2 [84]. Cathepsin S also evoked a calcium response in mouse DRG neurons, which is reduced by PAR-2 antagonists and in TRPV1-/-or TRPA1-/-mouse-derived DRGs. In addition, intradermal injection of cathepsin S induced scratching behavior, which was inhibited by the cathepsin S inhibitor LHVS [17].

    3.3. Peptides

    3.3.1. Substance P

    Substance P (SP) is a short neuropeptide of the tachykinin family, consisting of 11 amino acids (Arg-Pro-Lys-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2), and is one of most potent pruritogens identified to date [98][99]. SP is expressed by many cell types, including sensory neurons, astrocytes, microglia, epithelial cells, endothelial cells and immune cells, including T cells, macrophages, DCs and eosinophils [11][50][100]. SP binds to neurokinin 1 receptor (NK-1R) and another class of receptors involved in itch signaling, consisting of mouse MrgprA1, mouse MrgprB2 and human MrgprX2. NK-1R is a tachykinin receptor belonging to the GPCR family and expressed in the CNS, keratinocytes, fibroblasts and mast cells [98][99]. In humans, SP promotes degranulation by binding to mast cell NK-1R, releasing histamine and LTB4 and causing itch [52][99]. In mice, SP induces itch through direct action on primary sensory neurons, as well as by release of nitric oxide (NO) and LTB4 from keratinocytes, rather than by mast cell degranulation [52][101].

    3.3.2. Endothelin-1

    Endothelin (ET)-1 is a 21 amino-acid peptide member of the endothelin family and a potent pruritogen that can elicit scratching at low concentration (10–400 pmol/site) [102][103][104]. ET-1 is produced by mast cells, endothelial cells and keratinocytes in the skin [82][102][103][104]. ETs have two active receptors, ETA and ETB, which belong to the GPCR superfamily [104][105][106]. Endothelin receptors are widely expressed in all tissues [107], and ET-1-evoked scratching is mediated by ETA [102]. In addition, the endothelin receptor antagonist bosentan inhibited symptoms including itch in AD model mice [19].

    3.4. Cytokines

    3.4.1. IL-2

    Interleukin (IL)-2 is a 15.5 kDa cytokine secreted by antigen-activated CD4+ T cells and mast cells [108][109][110][20]. It was first described as a T cell growth factor and later also found to have the ability to act on natural killer (NK) cells and NKT cells, to activate B cells, and to induce the proliferation of regulatory T cells (Tregs), innate lymphoid cells (ILCs) and effector T cells. IL-2 has three receptors, each of which is composed of three subunits: IL-2 receptor α (IL-2Rα, CD25), IL-2Rβ (CD122), and IL-2Rγ (CD132). IL-2Rα is expressed by several types of immune cells, including Tregs, ILC2, activated CD4+ and CD8+ T cells, B cells, CD56hi NK cells, mature DCs, and endothelial cells. IL-2Rβ is mainly expressed by multiple lymphoid populations, such as Tregs, memory CD8+ T cells, NK cells, and NKT cells, and to some extent, by monocytes and neutrophils. IL-2Rγ is expressed mostly by hematopoietic cells [108][20][21]. The binding of IL-2 to its receptors induces trans-phosphorylation of Janus kinase (JAK) 1 and JAK3. This, in turn, activates the JAK/signal transducer and activator of transcription (STAT), phosphoinositide (PI) 3-kinase and MAPK signaling pathways [20][21]. Intravenous IL-2 treatment has been approved for the treatment of patients with metastatic melanoma and renal cell carcinoma, with beneficial results in a subset of patients, although severe pruritus is a known side effect [108][20][21][111][22]. Moreover, intradermal injection of IL-2 in either healthy subjects or patients with AD induced pruritus and erythema [22][112]. The calcineurin inhibitor cyclosporine A has been shown to downregulate IL-2 synthesis, reducing pruritus in patients with treatment resistant Sezary syndrome, as well as in patients with AD [22].

    3.4.2. IL-4

    IL-4 is a type 2 cytokine produced by T helper (Th) 2 cells, lymph node T follicular helper (Tfh) cells, mast cells, basophils, eosinophils and ILC2 [113][114][24][115]. IL-4 has two receptors, IL-4Rα (CD124) and the more common IL-4Rγ, with IL-4 having higher affinity to IL-4Rα [116]. IL-4 signals through the IL-4Rα/γC complex in hematopoietic cells, such as lymphocytes and DCs. IL-4 binds IL-4Rα/γC and activates the downstream signaling molecules JAK1/JAK3 and then STAT6. Non-hematopoietic cells including keratinocytes also express IL-4Rα/IL-13Rα1 complex, which binds both IL-4 and IL-13, resulting in the downstream activation of JAK1/TYK2/JAK2 and then STAT6/STAT3 [24]. IL-4-evoked mouse DRG neurons respond to calcium, and deletion of IL-4Ra on sensory neurons was found to disrupt scratching behavior in a mouse model of AD. Moreover, IL-4 has been suggested as a modulator of itch because it enhances itch by increasing the neural responses induced by histamine, chloroquine, TSLP, and IL-31 [13][113]. Intradermal administration of IL-4 has also been reported to induce itching and alloknesis [117][118]. Dupilumab, a monoclonal antibody that binds specifically to the shared alpha chain subunit of the IL-4 and IL-13 receptors, was associated with improvements in clinical end points, including reduced pruritus in AD [119].

    3.4.3. IL-13

    IL-13 is another type 2 cytokine produced by Th2, ILC2, mast cells, basophils, and eosinophils [113][114][24][115]. It has two receptors, IL-13Rα1 (CD213α1) and IL-13Rα2 (CD213α2). IL-13Rα1 alone binds IL-13 with low affinity, but when paired with IL-4Rα it binds IL-13 with high affinity and forms a functional IL-13 receptor that signals and results in activation of STAT3/6 [24][25]. Similar to IL-4, intradermal administration of IL-13 has been reported to induce itching and alloknesis [117][118].
    To date, the role of IL-13Rα2 in itch has been unclear. However, a recent study showed that the expression of IL-13Rα2 is upregulated in the skin of patients with AD, but not in the skin of patients with psoriasis, in a disease activity-dependent manner. In keratinocytes, IL-13 regulated IL-13Rα2 expression level and promoted IL-13Rα2 signaling. In addition, TLR2 activation was found to increase IL-13 mediated itch by potentiating IL-13Rα2, suggesting that IL-13Rα2 signaling promotes AD symptoms including itch [120]. Monoclonal antibodies that target and neutralize IL-13, Tralokinumab and Lebrikizumab, both improved AD symptoms including itch [14].

    3.5. Lipid Mediators

    3.5.1. PAF

    Platelet-activating factor (PAF) is produced and released by mast cells, basophils, neutrophils, eosinophils, monocytes, macrophages, fibroblasts, platelets, endothelial cells, and cardiac muscle cells, all of which play important roles in inflammatory and thrombotic diseases. PAF is an inflammatory factor and has important functions in acute and chronic inflammation [121][39]. PAF receptor (PAFR) has been found in a host of cell membranes, including those of platelets, neutrophils, macrophages, mononuclear leukocytes, and eosinophils, as well as on hippocampal nerves, microglia, astrocytes, and oligodendrocyte progenitor cells [39]. Intradermal PAF injection evoked scratching behavior [64][122] and induced histamine release through degranulation of mast cells, contributing to itch accompanied by flare and wheal reactions [123].

    3.5.2. LTB4

    Leukotrienes (LTs) are eicosanoid lipid mediators generated upon activation of both immune and structural cells such as epithelial cells and endothelial cells. LTB4, a 5-lipoxygenase metabolite, is increased in the skin of AD model mice [124]. This molecule is produced and released by various types of immune cells, including mast cells, basophils, eosinophils, and macrophages [125][126][127][128]. LTB4 has two receptors, BLT1 and BLT2, which are GPCR and present on cell surfaces, with BLT1 having higher affinity and activity than BLT2. BLT1 is mainly expressed by leukocytes and DRG neurons, whereas BLT2 is expressed on many tissues [129][130][41]. LTB4-induced DRG neurons respond to calcium, an effect inhibited by the LTB4 antagonist ONO-4057 [41]. Intradermal LTB4 injection induces scratching via TRPA1 and TRPV1 [131]. Moreover, the LTB4 receptor antagonist CMHVA attenuated IL-31-induced scratching [42].

    3.5.3. LTC4

    LTC4 is a cysteinyl LT produced and released by mast cells, basophils, and eosinophils [132][133][134]. Its receptors, CysLTR1 and CysLTR2, are widely expressed by hematopoietic and structural cells [12]. Basophils have been shown to release LTC4 upon stimulation with antigen-specific IgE, which binds to CysLTR2 expressed on sensory nerve fibers (mainly NP3 nerves), evoking acute severe itch (itch flares) of AD [133]. Moreover, the LTC4/CysLTR2 pathway was shown to contribute not only to acute but also to chronic itch [12].
    3.6. Others
    3.6.1. IL-33
    IL-33, a member of the IL-1 cytokine family, is considered important for host defenses and allergy by inducing Th2 cytokine production via the IL-33 receptor. This receptor is a heterodimer composed of IL-1 receptor-like 1 (IL-1RL1; also called ST2) and IL-1 receptor accessory protein (IL-1RAcP) molecules. IL-33 was first identified as a nuclear protein expressed in endothelial cell nuclei and was shown to be constitutively expressed in the nuclei of various cell types, such as endothelial and epithelial cells [134,135]. IL-33 was also recently shown to be constitutively expressed in other cells,
    including DCs, macrophages, mast cells, fibroblasts, smooth muscle cells, platelets and
    megakaryocytes [135,136]. ST2 expressing cells include basophils, mast cells, eosinophils, macrophages, DCs, NK cells, NKT cells, Th2 cells, cytotoxic T cells, Tregs, B cells, ILCs, microglia, astrocytes, neurons, epithelial cells, endothelial cells, and fibroblasts [135,137,138]. Treatment of AD model mice with anti-IL-33 antibody improved AD-like symptoms, including scratching behavior [139]. Moreover, IL-33/ST2 signaling was found to mediate chronic itch in a mouse model of contact hypersensitivity through the astrocytic JAK2/STAT3 cascade [140]. IL-33 was also shown to evoke calcium responses in neurons, with enhanced CQ evoking calcium responses [138]. Taken together, these findings suggested that IL-33 also functions as a modulator to enhance itch.
    3.6.2. TSLP
    Thymic stromal lymphopoietin (TSLP) is a IL-7 like cytokine belonging to the IL-2 cytokine family [110,141]. It is primarily produced by epithelial cells, including keratinocytes, fibroblasts and stromal cells, as well as by DCs, mast cells, and basophils [110,142]. Its receptor, TSLPR, is expressed on monocytes/macrophages, T cells, B cells, mast cells, eosinophils, NK cells, DCs, keratinocytes and sensory neuronal endings [143–148]. TSLPR is activated upon binding of TSLP, which activates JAK1/2 and STAT1/3/4/5/6 [149,150]. Intradermal injection of TSLP evoked scratching behavior. This is initiated by the binding of TSLP to TSLPR expressed on sensory nerve fibers. The TSLP-induced itch also required TRPA1, with the expression and release of keratinocyte-derived TSLP depending on the ORAI1/NFAT calcium signaling pathway [148]. Epithelial cell-derived cytokines, including TSLP and IL-33, strongly activate ILC2 and recruit Th2 cells into the skin. ILC2 and Th2 cells are rich sources of type 2 cytokines, which can initiate and perpetuate allergic skin inflammation, including itch, by recruiting basophils and eosinophils [91].

    This entry is adapted from 10.3390/ijms222212365


    1. Ikoma, A. Updated neurophysiology of itch. Biol. Pharm. Bull. 2013, 36, 1235–1240.
    2. Mettang, T.; Kremer, A.E. Uremic pruritus. Kidney Int. 2015, 87, 685–691.
    3. Dull, M.M.; Kremer, A.E. Treatment of Pruritus Secondary to Liver Disease. Curr. Gastroenterol. Rep. 2019, 21, 48.
    4. Iwamoto, S.; Tominaga, M.; Kamata, Y.; Kawakami, T.; Osada, T.; Takamori, K. Association Between Inflammatory Bowel Disease and Pruritus. Crohns Colitis 360 2020, 2, otaa012.
    5. Greaves, M.W. Itch in systemic disease: Therapeutic options. Dermatol. Ther. 2005, 18, 323–327.
    6. Ikoma, A.; Steinhoff, M.; Stander, S.; Yosipovitch, G.; Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 2006, 7, 535–547.
    7. Paus, R.; Schmelz, M.; Biro, T.; Steinhoff, M. Frontiers in pruritus research: Scratching the brain for more effective itch therapy. J. Clin. Investig. 2006, 116, 1174–1186.
    8. Basbaum, A.I.; Bautista, D.M.; Scherrer, G.; Julius, D. Cellular and molecular mechanisms of pain. Cell 2009, 139, 267–284.
    9. Usoskin, D.; Furlan, A.; Islam, S.; Abdo, H.; Lonnerberg, P.; Lou, D.; Hjerling-Leffler, J.; Haeggstrom, J.; Kharchenko, O.; Kharchenko, P.V.; et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat. Neurosci. 2015, 18, 145–153.
    10. Liu, Q.; Sikand, P.; Ma, C.; Tang, Z.; Han, L.; Li, Z.; Sun, S.; LaMotte, R.H.; Dong, X. Mechanisms of itch evoked by beta-alanine. J. Neurosci. 2012, 32, 14532–14537.
    11. Choi, J.E.; Di Nardo, A. Skin neurogenic inflammation. Semin. Immunopathol. 2018, 40, 249–259.
    12. Voisin, T.; Perner, C.; Messou, M.A.; Shiers, S.; Ualiyeva, S.; Kanaoka, Y.; Price, T.J.; Sokol, C.L.; Bankova, L.G.; Austen, K.F.; et al. The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch. Proc. Natl. Acad. Sci. USA 2021, 118.
    13. Oetjen, L.K.; Mack, M.R.; Feng, J.; Whelan, T.M.; Niu, H.; Guo, C.J.; Chen, S.; Trier, A.M.; Xu, A.Z.; Tripathi, S.V.; et al. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell 2017, 171, 217–228.e13.
    14. Iannone, M.; Tonini, G.; Janowska, A.; Dini, V.; Romanelli, M. Definition of treatment goals in terms of clinician-reported disease severity and patient-reported outcomes in moderate-to-severe adult atopic dermatitis: A systematic review. Curr. Med. Res. Opin. 2021, 37, 1295–1301.
    15. Bolier, A.R.; Peri, S.; Oude Elferink, R.P.; Beuers, U. The challenge of cholestatic pruritus. Acta Gastroenterol. Belg. 2012, 75, 399–404.
    16. Sharma, R.; Prasad, V.; McCarthy, E.T.; Savin, V.J.; Dileepan, K.N.; Stechschulte, D.J.; Lianos, E.; Wiegmann, T.; Sharma, M. Chymase increases glomerular albumin permeability via protease-activated receptor-2. Mol. Cell. Biochem. 2007, 297, 161–169.
    17. Chung, K.; Pitcher, T.; Grant, A.D.; Hewitt, E.; Lindstrom, E.; Malcangio, M. Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour. Neurobiol. Pain 2019, 6, 100032.
    18. Pariser, D.M.; Bagel, J.; Lebwohl, M.; Yosipovitch, G.; Chien, E.; Spellman, M.C. Serlopitant for psoriatic pruritus: A phase 2 randomized, double-blind, placebo-controlled clinical trial. J. Am. Acad. Dermatol. 2020, 82, 1314–1320.
    19. Kido-Nakahara, M.; Wang, B.; Ohno, F.; Tsuji, G.; Ulzii, D.; Takemura, M.; Furue, M.; Nakahara, T. Inhibition of mite-induced dermatitis, pruritus, and nerve sprouting in mice by the endothelin receptor antagonist bosentan. Allergy 2021, 76, 291–301.
    20. Mitra, S.; Leonard, W.J. Biology of IL-2 and its therapeutic modulation: Mechanisms and strategies. J. Leukoc. Biol. 2018, 103, 643–655.
    21. Wrangle, J.M.; Patterson, A.; Johnson, C.B.; Neitzke, D.J.; Mehrotra, S.; Denlinger, C.E.; Paulos, C.M.; Li, Z.; Cole, D.J.; Rubinstein, M.P. IL-2 and Beyond in Cancer Immunotherapy. J. Interferon Cytokine Res. 2018, 38, 45–68.
    22. Mollanazar, N.K.; Smith, P.K.; Yosipovitch, G. Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? Clin. Rev. Allergy Immunol. 2016, 51, 263–292.
    23. Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Kaino, H.; Nagata, T. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J. Am. Acad. Dermatol. 2020, 82, 823–831.
    24. Furue, M. Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4JAKSTAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis. J. Clin. Med. 2020, 9, 3741.
    25. Tabata, Y.; Hershey, G.K.K. IL-13 receptor isoforms: Breaking through the complexity. Curr. Allergy Asthm. Rep. 2007, 7, 338–345.
    26. Silverberg, J.I.; Yosipovitch, G.; Simpson, E.L.; Kim, B.S.; Wu, J.J.; Eckert, L.; Guillemin, I.; Chen, Z.; Ardeleanu, M.; Bansal, A.; et al. Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS. J. Am. Acad. Dermatol. 2020, 82, 1328–1336.
    27. Gottlieb, A.B.; Gordon, K.; Hsu, S.; Elewski, B.; Eichenfield, L.F.; Kircik, L.; Rastogi, S.; Pillai, R.; Israel, R. Improvement in itch and other psoriasis symptoms with brodalumab in phase 3 randomized controlled trials. J. Eur. Acad. Dermatol. Venereol. 2018, 32, 1305–1313.
    28. Parham, C.; Chirica, M.; Timans, J.; Vaisberg, E.; Travis, M.; Cheung, J.; Pflanz, S.; Zhang, R.; Singh, K.P.; Vega, F.; et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 2002, 168, 5699–5708.
    29. Vignali, D.A.; Kuchroo, V.K. IL-12 family cytokines: Immunological playmakers. Nat. Immunol. 2012, 13, 722–728.
    30. Datsi, A.; Steinhoff, M.; Ahmad, F.; Alam, M.; Buddenkotte, J. Interleukin-31: The “itchy” cytokine in inflammation and therapy. Allergy 2021, 76, 2982–2997.
    31. Zhang, Q.; Putheti, P.; Zhou, Q.; Liu, Q.; Gao, W. Structures and biological functions of IL-31 and IL-31 receptors. Cytokine Growth Factor Rev. 2008, 19, 347–356.
    32. Cevikbas, F.; Wang, X.; Akiyama, T.; Kempkes, C.; Savinko, T.; Antal, A.; Kukova, G.; Buhl, T.; Ikoma, A.; Buddenkotte, J.; et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J. Allergy Clin. Immunol. 2014, 133, 448–460.
    33. Furue, M.; Yamamura, K.; Kido-Nakahara, M.; Nakahara, T.; Fukui, Y. Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis. Allergy 2018, 73, 29–36.
    34. Kabashima, K.; Matsumura, T.; Komazaki, H.; Kawashima, M.; Nemolizumab, J.P.S.G. Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus. N. Engl. J. Med. 2020, 383, 141–150.
    35. Du, L.; Hu, X.; Yang, W.; Yasheng, H.; Liu, S.; Zhang, W.; Zhou, Y.; Cui, W.; Zhu, J.; Qiao, Z.; et al. Spinal IL-33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2-STAT3 cascade. Glia 2019, 67, 1680–1693.
    36. Rochman, Y.; Kashyap, M.; Robinson, G.W.; Sakamoto, K.; Gomez-Rodriguez, J.; Wagner, K.U.; Leonard, W.J. Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling. Proc. Natl. Acad. Sci. USA 2010, 107, 19455–19460.
    37. Arima, K.; Watanabe, N.; Hanabuchi, S.; Chang, M.; Sun, S.C.; Liu, Y.J. Distinct signal codes generate dendritic cell functional plasticity. Sci. Signal. 2010, 3, ra4.
    38. Ratchataswan, T.; Banzon, T.M.; Thyssen, J.P.; Weidinger, S.; Guttman-Yassky, E.; Phipatanakul, W. Biologics for Treatment of Atopic Dermatitis: Current Status and Future Prospect. J. Allergy Clin. Immunol. Pract. 2021, 9, 1053–1065.
    39. Liu, Y.; Shields, L.B.E.; Gao, Z.; Wang, Y.; Zhang, Y.P.; Chu, T.; Zhu, Q.; Shields, C.B.; Cai, J. Current Understanding of Platelet-Activating Factor Signaling in Central Nervous System Diseases. Mol. Neurobiol. 2017, 54, 5563–5572.
    40. Abeck, D.; Andersson, T.; Grosshans, E.; Jablonska, S.; Kragballe, K.; Vahlquist, A.; Schmidt, T.; Dupuy, P.; Ring, J. Topical application of a platelet-activating factor (PAF) antagonist in atopic dermatitis. Acta Derm. Venereol. 1997, 77, 449–451.
    41. Andoh, T.; Kuraishi, Y. Expression of BLT1 leukotriene B4 receptor on the dorsal root ganglion neurons in mice. Mol. Brain Res. 2005, 137, 263–266.
    42. Andoh, T.; Harada, A.; Kuraishi, Y. Involvement of Leukotriene B4 Released from Keratinocytes in Itch-associated Response to Intradermal Interleukin-31 in Mice. Acta Derm. Venereol. 2017, 97, 922–927.
    43. Itadani, S.; Takahashi, S.; Ima, M.; Sekiguchi, T.; Fujita, M.; Nakayama, Y.; Takeuchi, J. Discovery of Highly Potent Dual CysLT1 and CysLT2 Antagonist. ACS Med. Chem. Lett. 2014, 5, 1230–1234.
    44. MacGlashan, D. Histamine. J. Allergy Clin. Immunol. 2003, 112, S53–S59.
    45. Ringvall, M.; Ronnberg, E.; Wernersson, S.; Duelli, A.; Henningsson, F.; Abrink, M.; Garcia-Faroldi, G.; Fajardo, I.; Pejler, G. Serotonin and histamine storage in mast cell secretory granules is dependent on serglycin proteoglycan. J. Allergy Clin. Immunol. 2008, 121, 1020–1026.
    46. Shimizu, K.; Andoh, T.; Yoshihisa, Y.; Shimizu, T. Histamine released from epidermal keratinocytes plays a role in alpha-melanocyte-stimulating hormone-induced itching in mice. Am. J. Pathol. 2015, 185, 3003–3010.
    47. Yosipovitch, G.; Rosen, J.D.; Hashimoto, T. Itch: From mechanism to (novel) therapeutic approaches. J. Allergy Clin. Immunol. 2018, 142, 1375–1390.
    48. Kabashima, K.; Nakashima, C.; Nonomura, Y.; Otsuka, A.; Cardamone, C.; Parente, R.; De Feo, G.; Triggiani, M. Biomarkers for evaluation of mast cell and basophil activation. Immunol. Rev. 2018, 282, 114–120.
    49. Hashimoto, T.; Rosen, J.D.; Sanders, K.M.; Yosipovitch, G. Possible roles of basophils in chronic itch. Exp. Dermatol. 2019, 28, 1373–1379.
    50. Nakashima, C.; Ishida, Y.; Kitoh, A.; Otsuka, A.; Kabashima, K. Interaction of peripheral nerves and mast cells, eosinophils, and basophils in the development of pruritus. Exp. Dermatol. 2019, 28, 1405–1411.
    51. Moriguchi, T.; Takai, J. Histamine and histidine decarboxylase: Immunomodulatory functions and regulatory mechanisms. Genes Cells 2020, 25, 443–449.
    52. Akiyama, T.; Carstens, E. Neural processing of itch. Neuroscience 2013, 250, 697–714.
    53. Yamashita, M.; Fukui, H.; Sugama, K.; Horio, Y.; Ito, S.; Mizuguchi, H.; Wada, H. Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc. Natl. Acad. Sci. USA 1991, 88, 11515–11519.
    54. Oda, T.; Morikawa, N.; Saito, Y.; Masuho, Y.; Matsumoto, S. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J. Biol. Chem. 2000, 275, 36781–36786.
    55. Hough, L.B. Genomics meets histamine receptors: New subtypes, new receptors. Mol. Pharmacol. 2001, 59, 415–419.
    56. Ohsawa, Y.; Hirasawa, N. The role of histamine H1 and H4 receptors in atopic dermatitis: From basic research to clinical study. Allergol. Int. 2014, 63, 533–542.
    57. Shim, W.S.; Tak, M.H.; Lee, M.H.; Kim, M.; Kim, M.; Koo, J.Y.; Lee, C.H.; Kim, M.; Oh, U. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J. Neurosci. 2007, 27, 2331–2337.
    58. Rossbach, K.; Nassenstein, C.; Gschwandtner, M.; Schnell, D.; Sander, K.; Seifert, R.; Stark, H.; Kietzmann, M.; Baumer, W. Histamine H1, H3 and H4 receptors are involved in pruritus. Neuroscience 2011, 190, 89–102.
    59. Sommer, C. Serotonin in pain and analgesia: Actions in the periphery. Mol. Neurobiol. 2004, 30, 117–125.
    60. Conti, P.; Shaik-Dasthagirisaheb, Y.B. Mast Cell Serotonin Immunoregulatory Effects Impacting on Neuronal Function: Implications for Neurodegenerative and Psychiatric Disorders. Neurotox. Res. 2015, 28, 147–153.
    61. Domocos, D.; Selescu, T.; Ceafalan, L.C.; Iodi Carstens, M.; Carstens, E.; Babes, A. Role of 5-HT1A and 5-HT3 receptors in serotonergic activation of sensory neurons in relation to itch and pain behavior in the rat. J. Neurosci. Res. 2020, 98, 1999–2017.
    62. Akiyama, T.; Ivanov, M.; Nagamine, M.; Davoodi, A.; Carstens, M.I.; Ikoma, A.; Cevikbas, F.; Kempkes, C.; Buddenkotte, J.; Steinhoff, M.; et al. Involvement of TRPV4 in Serotonin-Evoked Scratching. J. Investig. Dermatol. 2016, 136, 154–160.
    63. Yamaguchi, T.; Nagasawa, T.; Satoh, M.; Kuraishi, Y. Itch-associated response induced by intradermal serotonin through 5-HT2 receptors in mice. Neurosci. Res. 1999, 35, 77–83.
    64. Thomsen, J.S.; Petersen, M.B.; Benfeldt, E.; Jensen, S.B.; Serup, J. Scratch induction in the rat by intradermal serotonin: A model for pruritus. Acta Derm. Venereol. 2001, 81, 250–254.
    65. Jinks, S.L.; Carstens, E. Responses of superficial dorsal horn neurons to intradermal serotonin and other irritants: Comparison with scratching behavior. J. Neurophysiol. 2002, 87, 1280–1289.
    66. Nojima, H.; Carstens, E. 5-Hydroxytryptamine (5-HT)2 receptor involvement in acute 5-HT-evoked scratching but not in allergic pruritus induced by dinitrofluorobenzene in rats. J. Pharmacol. Exp. Ther. 2003, 306, 245–252.
    67. Hu, W.P.; Guan, B.C.; Ru, L.Q.; Chen, J.G.; Li, Z.W. Potentiation of 5-HT3 receptor function by the activation of coexistent 5-HT2 receptors in trigeminal ganglion neurons of rats. Neuropharmacology 2004, 47, 833–840.
    68. Machida, T.; Iizuka, K.; Hirafuji, M. Recent Advances in 5-Hydroxytryptamine (5-HT) Receptor Research: How Many Pathophysiological Roles Does 5-HT Play via Its Multiple Receptor Subtypes? Biol. Pharm. Bull 2013, 36, 1416–1419.
    69. Cortes-Altamirano, J.L.; Olmos-Hernandez, A.; Jaime, H.B.; Carrillo-Mora, P.; Bandala, C.; Reyes-Long, S.; Alfaro-Rodriguez, A. Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 Receptors and their Role in the Modulation of Pain Response in the Central Nervous System. Curr. Neuropharmacol. 2018, 16, 210–221.
    70. Caughey, G.H.; Raymond, W.W.; Blount, J.L.; Hau, L.W.; Pallaoro, M.; Wolters, P.J.; Verghese, G.M. Characterization of human gamma-tryptases, novel members of the chromosome 16p mast cell tryptase and prostasin gene families. J. Immunol. 2000, 164, 6566–6575.
    71. Wong, G.W.; Yasuda, S.; Madhusudhan, M.S.; Li, L.; Yang, Y.; Krilis, S.A.; Sali, A.; Stevens, R.L. Human tryptase epsilon (PRSS22), a new member of the chromosome 16p13.3 family of human serine proteases expressed in airway epithelial cells. J. Biol. Chem. 2001, 276, 49169–49182.
    72. Caughey, G.H. Tryptase genetics and anaphylaxis. J. Allergy Clin. Immunol. 2006, 117, 1411–1414.
    73. Hernandez-Hernandez, L.; Sanz, C.; Garcia-Solaesa, V.; Padron, J.; Garcia-Sanchez, A.; Davila, I.; Isidoro-Garcia, M.; Lorente, F. Tryptase: Genetic and functional considerations. Allergol. Immunopathol. 2012, 40, 385–389.
    74. Caughey, G.H. The structure and airway biology of mast cell proteinases. Am. J. Respir. Cell. Mol. Biol. 1991, 4, 387–394.
    75. Nadel, J.A. Biologic effects of mast cell enzymes. Am. Rev. Respir. Dis. 1992, 145, S37–S41.
    76. Xia, H.Z.; Kepley, C.L.; Sakai, K.; Chelliah, J.; Irani, A.M.; Schwartz, L.B. Quantitation of Tryptase, Chymase, Fc~Rlcu, and FcεRlγ mRNAs in Human Mast Cells and Basophils by Competitive Reverse Transcription-Polymerase Chain Reaction. J. Immunol. 1995, 154, 5472–5480.
    77. Jogie-Brahim, S.; Min, H.K.; Fukuoka, Y.; Xia, H.Z.; Schwartz, L.B. Expression of alpha-tryptase and beta-tryptase by human basophils. J. Allergy Clin. Immunol. 2004, 113, 1086–1092.
    78. Ui, H.; Andoh, T.; Lee, J.B.; Nojima, H.; Kuraishi, Y. Potent pruritogenic action of tryptase mediated by PAR-2 receptor and its involvement in anti-pruritic effect of nafamostat mesilate in mice. Eur. J. Pharmacol. 2006, 530, 172–178.
    79. Lee, S.E.; Jeong, S.K.; Lee, S.H. Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis. Yonsei Med. J. 2010, 51, 808–822.
    80. Heuberger, D.M.; Schuepbach, R.A. Protease-activated receptors (PARs): Mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb. J. 2019, 17, 4.
    81. Klein, A.; Carstens, M.I.; Carstens, E. Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons. J. Neurophysiol. 2011, 106, 1078–1088.
    82. Gupta, K.; Harvima, I.T. Mast cell-neural interactions contribute to pain and itch. Immunol. Rev. 2018, 282, 168–187.
    83. Thapaliya, M.; Chompunud Na Ayudhya, C.; Amponnawarat, A.; Roy, S.; Ali, H. Mast Cell-Specific MRGPRX2: A Key Modulator of Neuro-Immune Interaction in Allergic Diseases. Curr. Allergy Asthma. Rep. 2021, 21, 3.
    84. Akiyama, T.; Carstens, M.I.; Ikoma, A.; Cevikbas, F.; Steinhoff, M.; Carstens, E. Mouse model of touch-evoked itch (alloknesis). J. Investig. Dermatol. 2012, 132, 1886–1891.
    85. Gallwitz, M.; Enoksson, M.; Hellman, L. Expression profile of novel members of the rat mast cell protease (rMCP)-2 and (rMCP)-8 families, and functional analyses of mouse mast cell protease (mMCP)-8. Immunogenetics 2007, 59, 391–405.
    86. Atiakshin, D.; Buchwalow, I.; Tiemann, M. Mast cell chymase: Morphofunctional characteristics. Histochem. Cell Biol. 2019, 152, 253–269.
    87. Caughey, G.H. Mast cell tryptases and chymases in inflammation and host defense. Immunol. Rev. 2007, 217, 141–154.
    88. Caughey, G.H. Mast cell proteases as protective and inflammatory mediators. Adv. Exp. Med. Biol. 2011, 716, 212–234.
    89. Wasse, H.; Naqvi, N.; Husain, A. Impact of Mast Cell Chymase on Renal Disease Progression. Curr. Hypertens. Rev. 2012, 8, 15–23.
    90. De Souza Junior, D.A.; Santana, A.C.; da Silva, E.Z.; Oliver, C.; Jamur, M.C. The Role of Mast Cell Specific Chymases and Tryptases in Tumor Angiogenesis. Biomed. Res. Int. 2015, 2015, 142359.
    91. Nabe, T.; Kijitani, Y.; Kitagawa, Y.; Sakano, E.; Ueno, T.; Fujii, M.; Nakao, S.; Sakai, M.; Takai, S. Involvement of chymase in allergic conjunctivitis of guinea pigs. Exp. Eye Res. 2013, 113, 74–79.
    92. Imada, T.; Komorita, N.; Kobayashi, F.; Naito, K.; Yoshikawa, T.; Miyazaki, M.; Nakamura, N.; Kondo, T. Therapeutic potential of a specific chymase inhibitor in atopic dermatitis. Jpn. J. Pharmacol. 2002, 90, 214–217.
    93. Schwarz, G.; Boehncke, W.H.; Braun, M.; Schroter, C.J.; Burster, T.; Flad, T.; Dressel, D.; Weber, E.; Schmid, H.; Kalbacher, H. Cathepsin S activity is detectable in human keratinocytes and is selectively upregulated upon stimulation with interferon-gamma. J. Investig. Dermatol. 2002, 119, 44–49.
    94. Viode, C.; Lejeune, O.; Turlier, V.; Rouquier, A.; Casas, C.; Mengeaud, V.; Redoules, D.; Schmitt, A.M. Cathepsin S, a new pruritus biomarker in clinical dandruff/seborrhoeic dermatitis evaluation. Exp. Dermatol. 2014, 23, 274–275.
    95. Reddy, V.B.; Shimada, S.G.; Sikand, P.; Lamotte, R.H.; Lerner, E.A. Cathepsin S elicits itch and signals via protease-activated receptors. J. Investig. Dermatol. 2010, 130, 1468–1470.
    96. Reddy, V.B.; Sun, S.; Azimi, E.; Elmariah, S.B.; Dong, X.; Lerner, E.A. Redefining the concept of protease-activated receptors: Cathepsin S evokes itch via activation of Mrgprs. Nat. Commun. 2015, 6, 7864.
    97. Patricio, E.S.; Costa, R.; Figueiredo, C.P.; Gers-Barlag, K.; Bicca, M.A.; Manjavachi, M.N.; Segat, G.C.; Gentry, C.; Luiz, A.P.; Fernandes, E.S.; et al. Mechanisms Underlying the Scratching Behavior Induced by the Activation of Proteinase-Activated Receptor-4 in Mice. J. Investig. Dermatol. 2015, 135, 2484–2491.
    98. Lotts, T.; Stander, S. Research in practice: Substance P antagonism in chronic pruritus. J. Dtsch. Dermatol. Ges. 2014, 12, 557–559.
    99. Stander, S.; Yosipovitch, G. Substance P and neurokinin 1 receptor are new targets for the treatment of chronic pruritus. Br. J. Dermatol. 2019, 181, 932–938.
    100. Mashaghi, A.; Marmalidou, A.; Tehrani, M.; Grace, P.M.; Pothoulakis, C.; Dana, R. Neuropeptide substance P and the immune response. Cell Mol. Life Sci. 2016, 73, 4249–4264.
    101. Andoh, T.; Nagasawa, T.; Satoh, M.; Kuraishi, Y. Substance P induction of itch-associated response mediated by cutaneous NK1 tachykinin receptors in mice. J. Pharmacol. Exp. Ther. 1998, 286, 1140–1145.
    102. McQueen, D.S.; Noble, M.A.; Bond, S.M. Endothelin-1 activates ETA receptors to cause reflex scratching in BALB/c mice. Br. J. Pharmacol. 2007, 151, 278–284.
    103. Gomes, L.O.; Hara, D.B.; Rae, G.A. Endothelin-1 induces itch and pain in the mouse cheek model. Life Sci. 2012, 91, 628–633.
    104. Davenport, A.P.; Hyndman, K.A.; Dhaun, N.; Southan, C.; Kohan, D.E.; Pollock, J.S.; Pollock, D.M.; Webb, D.J.; Maguire, J.J. Endothelin. Pharmacol. Rev. 2016, 68, 357–418.
    105. Arai, H.; Hori, S.; Aramoti, I.; Ohkubo, H.; Nakanishi, S. Cloning and expression og a cDNA encoding an endothelin receptor. Nature 1990, 348, 730–732.
    106. Sakurai, T.; Yanagisawa, M.; Takuwa, Y.; Miyazaki, H.; Kimura, S.; Goto, K.; Masaki, T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 1990, 348, 732–735.
    107. Davenport, A.P. International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol. Rev. 2002, 54, 219–226.
    108. Sim, G.C.; Radvanyi, L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev. 2014, 25, 377–390.
    109. Morita, H.; Arae, K.; Unno, H.; Miyauchi, K.; Toyama, S.; Nambu, A.; Oboki, K.; Ohno, T.; Motomura, K.; Matsuda, A.; et al. An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers. Immunity 2015, 43, 175–186.
    110. Salamon, P.; Shefler, I.; Moshkovits, I.; Munitz, A.; Horwitz Klotzman, D.; Mekori, Y.A.; Hershko, A.Y. IL-33 and IgE stimulate mast cell production of IL-2 and regulatory T cell expansion in allergic dermatitis. Clin. Exp. Allergy 2017, 47, 1409–1416.
    111. Fallahzadeh, M.K.; Roozbeh, J.; Geramizadeh, B.; Namazi, M.R. Interleukin-2 serum levels are elevated in patients with uremic pruritus: A novel finding with practical implications. Nephrol. Dial. Transplant. 2011, 26, 3338–3344.
    112. Darsow, U.; Scharen, E.; Bromm, B.; Ring, J. Skin testing of the pruritogenic activity of histamine and cytoldnes (interIeukin-2 and tumour necrosis factor-a) at the dermal-epidermal junction. Br. J. Dermatol. 1997, 137, 415–417.
    113. Mack, M.R.; Kim, B.S. The Itch–Scratch Cycle: A Neuroimmune Perspective. Trends Immunol. 2018, 39, 980–991.
    114. Trier, A.M.; Mack, M.R.; Kim, B.S. The Neuroimmune Axis in Skin Sensation, Inflammation, and Immunity. J. Immunol. 2019, 202, 2829–2835.
    115. Garcovich, S.; Maurelli, M.; Gisondi, P.; Peris, K.; Yosipovitch, G.; Girolomoni, G. Pruritus as a Distinctive Feature of Type 2 Inflammation. Vaccines 2021, 9, 303.
    116. Nelms, K.; Keegan, A.D.; Zamorano, J.; Ryan, J.J.; Paul, W.E. The IL-4 receptor: Signaling mechanisms and biologic functions. Annu. Rev. Immunol. 1999, 17, 701–738.
    117. Campion, M.; Smith, L.; Gatault, S.; Metais, C.; Buddenkotte, J.; Steinhoff, M. Interleukin-4 and interleukin-13 evoke scratching behaviour in mice. Exp. Dermatol. 2019, 28, 1501–1504.
    118. Ichimasu, N.; Chen, Y.; Kobayashi, K.; Suzuki, S.; Chikazawa, S.; Shimura, S.; Katagiri, K. Possible involvement of type 2 cytokines in alloknesis in mouse models of menopause and dry skin. Exp. Dermatol. 2021, 30, 1745–1753.
    119. Simpson, E.L.; Bieber, T.; Guttman-Yassky, E.; Beck, L.A.; Blauvelt, A.; Cork, M.J.; Silverberg, J.I.; Deleuran, M.; Kataoka, Y.; Lacour, J.P.; et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N. Engl. J. Med. 2016, 375, 2335–2348.
    120. Xiao, S.; Lu, Z.; Steinhoff, M.; Li, Y.; Buhl, T.; Fischer, M.; Chen, W.; Cheng, W.; Zhu, R.; Yan, X.; et al. Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis. Brain Behav. Immun. 2021, 98, 28–39.
    121. Palgan, K.; Bartuzi, Z. Platelet activating factor in allergies. Int. J. Immunopathol. Pharmacol. 2015, 28, 584–589.
    122. Thomsen, J.S.; Sonne, M.; Benfeldt, E.; Jensen, S.B.; Serup, J.; Menne, T. Experimental itch in sodium lauryl sulphate-inflamed and normal skin in humans: A randomized, double-blind, placebo-controlled study of histamine and other inducers of itch. Br. J. Dermatol. 2002, 146, 792–800.
    123. Petersen, L.J.; Church, M.K.; Skov, P.S. Platelet-activating factor Induces histamine release from human skin mast cells in vivo, which is reduced by local nerve blockade. J. Allergy Clin. Immunol. 1997, 99, 640–647.
    124. Andoh, T.; Haza, S.; Saito, A.; Kuraishi, Y. Involvement of leukotriene B4 in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. Exp. Dermatol. 2011, 20, 894–898.
    125. Miyahara, N.; Ohnishi, H.; Miyahara, S.; Takeda, K.; Matsubara, S.; Matsuda, H.; Okamoto, M.; Loader, J.E.; Joetham, A.; Tanimoto, M.; et al. Leukotriene B4 release from mast cells in IgE-mediated airway hyperresponsiveness and inflammation. Am. J. Respir. Cell Mol. Biol. 2009, 40, 672–682.
    126. Bando, T.; Fujita, S.; Nagano, N.; Yoshikawa, S.; Yamanishi, Y.; Minami, M.; Karasuyama, H. Differential usage of COX-1 and COX-2 in prostaglandin production by mast cells and basophils. Biochem. Biophys. Rep. 2017, 10, 82–87.
    127. Pal, K.; Feng, X.; Steinke, J.W.; Burdick, M.D.; Shim, Y.M.; Sung, S.S.; Teague, W.G.; Borish, L. Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma. Am. J. Respir. Cell Mol. Biol. 2019, 60, 413–419.
    128. Finney-Hayward, T.K.; Bahra, P.; Li, S.; Poll, C.T.; Nicholson, A.G.; Russell, R.E.; Ford, P.A.; Westwick, J.; Fenwick, P.S.; Barnes, P.J.; et al. Leukotriene B4 release by human lung macrophages via receptor- not voltage-operated Ca2+ channels. Eur. Respir. J. 2009, 33, 1105–1112.
    129. Yokomizo, T.; Izumi, T.; Chang, K.; Takuwa, Y.; Shimizu, T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997, 387, 620–624.
    130. Yokomizo, T.; Kato, K.; Terawaki, K.; Izumi, T.; Shimizu, T. A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 2000, 192, 421–432.
    131. Fernandes, E.S.; Vong, C.T.; Quek, S.; Cheong, J.; Awal, S.; Gentry, C.; Aubdool, A.A.; Liang, L.; Bodkin, J.V.; Bevan, S.; et al. Superoxide generation and leukocyte accumulation: Key elements in the mediation of leukotriene B(4)-induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1. FASEB J. 2013, 27, 1664–1673.
    132. Murakami, M.; Matsumoto, R.; Urade, Y.; Austen, K.F.; Arm, J.P. c-kit ligand mediates increased expression of cytosolic phospholipase A2, prostaglandin endoperoxide synthase-1, and hematopoietic prostaglandin D2 synthase and increased IgE-dependent prostaglandin D2 generation in immature mouse mast cells. J. Biol. Chem. 1995, 270, 3239–3246.
    133. Wang, F.; Trier, A.M.; Li, F.; Kim, S.; Chen, Z.; Chai, J.N.; Mack, M.R.; Morrison, S.A.; Hamilton, J.D.; Baek, J.; et al. A basophil-neuronal axis promotes itch. Cell 2021, 184, 422–440.e417.
    134. Takafuji, S.; Bischoff, S.C.; De Weck, A.L.; Dahinden, C.A. IL-3 and IL-5 prime normal human eosinophils to produce leukotriene C4 in response to soluble agonists. J. Immunol. 1991, 147, 3855–3861.