Acute Itch Research Articles

The effect of TSLP, IgE and Eosinophil on Atopic Dermatitis Patients

Atopic dermatitis in another word Atopic Eczema is a chronic inflammatory skin disease that effecting all ages, described by lesions of eczematous and acute itch. As the objective of this study for determine the effect of variation in TSLP, IgE, and Eosinophil levels in patients with atopic dermatitis compared with a healthy control group. The level of TSLP was almost the same between the patients and the control group, and the reason was that most of the patients were treated with anti-allergic drugs. In this study, there is a significant (P = 0.004), serum level of TSLP in atopic dermatitis patient’s pre-treatment with immunotherapy (corticosteroids and antihistamines) is compared with atopic dermatitis patients’ post-treatment with immunotherapy and controls (23.06 vs. 29.48 and 23.99 pg/ml). The median level of overall T-IgE of the Atopic Dermatitis group was substantially greater than controls, (91.64 vs. 49.72 IU/ml), (P<0.023). Eosinophils count of Atopic Dermatitis patients was approximately equal to the control group, (3.1 ± 2.43 vs. 2.9 ± 1.05 %), (P-value 0.07). This study was conducted on a case series of 60 patients that have Atopic Dermatitis, who volunteered due to their review of the Allergy Center in Al-Rusafa, Baghdad, during the fall of 2020. Thirty healthy and non-Atopic Dermatitis volunteers of the same type, the center volunteered as a control group.

Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice

BackgroundHistamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells. ObjectiveDuring the Ph2b trial in AD, we performed experiments to understand the pharmacology of adriforant in primary murine cells and in vivo models. We assessed its effects on ERK phosphorylation and transcriptional changes in bone marrow-derived mast cells, histamine-dependent Ca2+ flux in neurons and histamine-induced itch response. In addition, its impact on MC903-induced skin inflammation was evaluated. ResultsWe show that, contrary to transfectants, adriforant is a competitive antagonist of the murine histamine receptor 4, antagonizes histamine-induced ERK phosphorylation, normalizes histamine-induced transcriptional changes in mast cells and reduces histamine-dependent Ca2+ flux in neurons. Administration to mice reduces acute histamine-induced itch response. In addition, adriforant ameliorates inflammation in the mouse MC903 model. ConclusionsOur results suggest that functional inhibition of histamine receptor 4 by adriforant reduces itch and inflammation in vivo. The effects observed in mice, however, did not translate to clinical efficacy in patients as the Ph2b clinical trial with adriforant did not meet pre-specified efficacy endpoints. Given the complex pathogenesis of AD, antagonism of histamine receptor 4 alone appears insufficient to reduce disease severity in AD patients, despite the effects seen in mouse models.

GABAergic neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet are involved in itch processing in mice

Itch and pain are two closely related sensations that receiving similar encodings at multiple levels. Accumulated evidences suggest that activation of the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL)-to-lateral and ventrolateral periaqueductal gray (l/vlPAG) projections mediates the antinociceptive effects of bright light therapy. Clinical study showed that bright light therapy may ameliorate cholestasis-induced pruritus. However, the underlying mechanism and whether this circuit participates in itch modulation remains unclear. In this study, chloroquine and histamine were utilized to induce acute itch models in mice. Neuronal activities in vLGN/IGL nucleus were evaluated with c-fos immunostaining as well as fiber photometry. Optogenetic manipulations were performed to activate or inhibit GABAergic neurons in the vLGN/IGL nucleus. Our results showed that the expressions of c-fos in vLGN/IGL were significantly increased upon both chloroquine- and histamine-induced acute itch stimuli. GABAergic neurons in vLGN/IGL were activated during histamine and chloroquine-induced scratching. Optogenetic activation of the vLGN/IGL GABAergic neurons exerts antipruritic effect, while inhibiting these neurons exerts pruritic effect. Our results provide evidence that GABAergic neurons in vLGN/IGL nucleus might play a crucial role in modulating itch, which may provide clue for application of bright light as an antipruritic treatment in clinic.

Excitatory Projections from the Prefrontal Cortex to Nucleus Accumbens Core D1-MSNs and κ Opioid Receptor Modulate Itch-Related Scratching Behaviors.

Itch is an uncomfortable and complex sensation that elicits the desire to scratch. The nucleus accumbens (NAc) activity is important in driving sensation, motivation, and emotion. Excitatory afferents from the medial prefrontal cortex (mPFC), amygdala, and hippocampus are crucial in tuning the activity of dopamine receptor D1-expressing and D2-expressing medium spiny neurons (Drd1-MSN and Drd2-MSN) in the NAc. However, a cell-type and neural circuity-based mechanism of the NAc underlying acute itch remains unclear. We found that acute itch induced by compound 48/80 (C48/80) decreased the intrinsic membrane excitability in Drd1-MSNs, but not in Drd2-MSNs, in the NAc core of male mice. Chemogenetic activation of Drd1-MSNs alleviated C48/80-induced scratching behaviors but not itch-related anxiety-like behaviors. In addition, C48/80 enhanced the frequency of spontaneous EPSCs (sEPSCs) and reduced the paired-pulse ratio (PPR) of electrical stimulation-evoked EPSCs in Drd1-MSNs. Furthermore, C48/80 increased excitatory synaptic afferents to Drd1-MSNs from the mPFC, not from the basolateral amygdala (BLA) or ventral hippocampus (vHipp). Consistently, the intrinsic excitability of mPFC-NAc projecting pyramidal neurons was increased after C48/80 treatment. Chemogenetic inhibition of mPFC-NAc excitatory synaptic afferents relieved the scratching behaviors. Moreover, pharmacological activation of κ opioid receptor (KOR) in the NAc core suppressed C48/80-induced scratching behaviors, and the modulation of KOR activity in the NAc resulted in the changes of presynaptic excitatory inputs to Drd1-MSNs in C48/80-treated mice. Together, these results reveal the neural plasticity in synapses of NAc Drd1-MSNs from the mPFC underlying acute itch and indicate the modulatory role of the KOR in itch-related scratching behaviors.SIGNIFICANCE STATEMENT Itch stimuli cause strongly scratching desire and anxiety in patients. However, the related neural mechanisms remain largely unclear. In the present study, we demonstrated that the pruritogen compound 48/80 (C48/80) shapes the excitability of dopamine receptor D1-expressing medium spiny neurons (Drd1-MSNs) in the nucleus accumbens (NAc) core and the glutamatergic synaptic afferents from medial prefrontal cortex (mPFC) to these neurons. Chemogenetic activation of Drd1-MSNs or inhibition of mPFC-NAc excitatory synaptic afferents relieves the scratching behaviors. In addition, pharmacological activation of κ opioid receptor (KOR) in the NAc core alleviates C48/80-induced itch. Thus, targeting mPFC-NAc Drd1-MSNs or KOR may provide effective treatments for itch.

Transient Receptor Potential Channels and Itch

Transient Receptor Potential (TRP) channels are multifunctional sensory molecules that are abundant in the skin and are involved in the sensory pathways of itch, pain, and inflammation. In this review article, we explore the complex physiology of different TRP channels, their role in modulating itch sensation, and their contributions to the pathophysiology of acute and chronic itch conditions. We also cover small molecule and topical TRP channel agents that are emerging as potential anti-pruritic treatments; some of which have shown great promise, with a few treatments advancing into clinical trials-namely, TRPV1, TRPV3, TRPA1, and TRPM8 targets. Lastly, we touch on possible ethnic differences in TRP channel genetic polymorphisms and how this may affect treatment response to TRP channel targets. Further controlled studies on the safety and efficacy of these emerging treatments is needed before clinical use.

An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in Mice

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex–midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

TRPV4 Activation Increases the Expression of CD207 (Langerin) of Monocyte-Derived Langerhans Cells without Affecting their Maturation

Langerhans cells (LCs) are the sole professional antigen-presenting cell normally found in the human epidermal compartment. Research into their physiological role is hindered by the fact that they are invariably activated during isolation from the skin. To overcome this challenge, we turned to a monocyte-derived LC (moLC) model, which we characterized with RNA sequencing, and compared the transcriptome of moLCs with that of donor-matched immature dendritic cells. We found that moLCs express markers characteristic of LC2 cells as well as TRPV4. TRPV4 is especially important in the skin because it has been linked to the conservation of the skin barrier, immunological responses, as well as acute and chronic itch, but we know little about its function on LCs. Our results show that TRPV4 activation increased the expression of Langerin and led to increased intracellular calcium concentration in moLCs. Regarding the functionality of moLCs, we found that TRPV4 agonism had a mitigating effect on their inflammatory responses because it decreased their cytokine production and T-cell activating capability. Because TRPV4 has emerged as a potential therapeutic target in dermatological conditions, it is important to highlight LCs as, to our knowledge, a previously unreported target of these therapies.

Anti-pruritic effect of isothiocyanates: Potential involvement of toll-like receptor 3 signaling.

The innate immune system has an emerging role as a mediator of neuro-immune communication and a therapeutic target for itch. Toll-like receptor 3 (TLR3) plays an important role in itch, as shown in TLR3 knock-out mice. In this study, to evaluate effects of TLR3 inhibitors on histamine-independent itch, we used two kinds of isothiocyanate (ITC). Both phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) inhibited Poly I:C (PIC)-induced signaling in the RAW264.7 cell line. We then investigated the anti-pruritic effect of these compounds on PIC- and chloroquine (CQ)-induced scratching behavior. PEITC and SFN both suppressed PIC-evoked scratching behavior in mice, and PEITC also inhibited CQ-induced acute itch. Finally, we examined the oxazolone-induced chronic itch model in mice. Surprisingly, oral dosing of both compounds suppressed scratching behaviors that were observed in mice. Our findings demonstrate that TLR3 is a critical mediator in acute and chronic itch transduction in mice and may be a promising therapeutic target for pruritus in human skin disorders. It is noteworthy that SFN has potential for use as an antipruritic as it is a phytochemical that is used as a supplement.

Keratinocyte TLR2 and TLR7 contribute to chronic itch through pruritic cytokines and chemokines in mice.

Although neuronal Toll-like receptors (TLRs) (e.g.,TLR2, TLR3, and TLR7) have been implicated in itch sensation, the roles of keratinocyte TLRs in chronic itch are elusive. Herein, we evaluated the roles of keratinocyte TLR2 and TLR7 in chronic itch under dry skin and psoriasis conditions, which was induced by either acetone-ether-water treatment or 5% imiquimod cream in mice, respectively. We found that TLR2 and TLR7 signaling were significantly upregulated in dry skin and psoriatic skin in mice. Chronic itch and epidermal hyperplasia induced by dry skin or psoriasis were comparably reduced in TLR2 and TLR7 knockout mice. In the dry skin model, the enhanced messenger RNA(mRNA) expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, TNF-α, and IFN-γ were inhibited in TLR2-/- mice, while CXCL2, IL-31, and IL-6 were inhibited in TLR7-/- mice. In psoriasis model, the enhanced mRNA expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, and TNF-α were inhibited in TLR2-/- mice, while CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, and TNF-α were inhibited in TLR7-/- mice. Incubation with Staphylococcus aureus (S. aureus) peptidoglycan (PGN-SA) (a TLR2 agonist), imiquimod (a TLR7 agonist), and miR142-3p (a putative TLR7 agonist) were sufficient to upregulate the expression of pruritic cytokines or chemokines in cultured keratinocyte HaCaT cells. Finally, pharmacological blockade of C-X-C Motif Chemokine Receptor 1/2 and high mobility group box protein 1 dose-dependently attenuated acute and chronic itch in mice. Together, these results indicate that keratinocyte TLR2 and TLR7 signaling pathways are distinctly involved in the pathogenesis of chronic itch.

Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice.

Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1 n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.

Corticotropin-releasing factor is involved in acute stress-induced analgesia and antipruritus.

Under the condition of stress, the hypothalamic-pituitary-adrenal axis (HPA axis) is activated and causes the secretion of corticotropin-releasing factor (CRF). Previous studies have demonstrated that CRF is involved in the regulation of pain and itch. Thus, it remains worthy to explore whether the desensitization of pain and itch under high-intensity acute stress (such as high fear and tension) is related to the sharp increase of CRF. Forced swimming was used to simulate acute stress. ELISA and pharmacological methods were conducted to observe the effects of forced swimming on acute pain or itch and the relationship between blood CRF content and itch or pain behavior. Intracerebroventricular (ICV) administration of CRF was conducted to examine the effects of CRF on acute pain or itch. Intrathecal administration of CRF receptor agonist or antagonist was conducted to examine the receptor mechanisms of the regulatory role of CRF in pain and itch. ELISA experiment showed that the serum CRF in mice reached its peak within 5-10 min after acute stress (forced swimming). Behavioral data showed that the scratching behavior induced by itch agents decreased after acute swimming, while the mechanical pain threshold increased significantly. The inhibitory effect of acute stress on pain and itch is mediated by CRF receptor2 (CRFR2). Then, ICV injection of CRF was used to simulate the massive release of CRF under acute stress, and we observed that the scratching behavior induced by histamine or chloroquine was significantly inhibited after ICV injection of CRF. The above effects of CRF are mainly mediated by CRFR2. These results suggest that 5-10min after acute stress, a large amount of CRF is released into the blood from the hypothalamus, which significantly inhibits acute pain and itch by acting on CRFR2. ICV injection of CRF can replicate the antipruritus effects of acute stress. The present study investigated the mechanism of acute stress-induced analgesia and antipruritus and provided theoretical support for the treatment of pain and itch.

Inhibitory effects of antibiotic-induced gut microbiota depletion on acute itch behavior in mice

BackgroundThe gut microbiota is known to be associated with the regulation of many neurological diseases and behaviors, including chronic pain. However, it is unclear whether the gut microbiota is critical to the itch sensation. In this study, we investigated the effects of gut microbiota depletion on acute itch. MethodsFirst, an antibiotic cocktail was orally administered to deplete the gut microbiota in male C57BL/6 mice. Then, pruritogens were intradermally injected to induce acute itch behavior. In addition, antibiotic-treated mice received transplantation of fecal microbiota from untreated mice, followed by tests for acute itch. The changes in c-Fos expression in trigeminal ganglia (TG) neurons were also investigated by immunofluorescence staining. ResultsOur results indicated that chronic antibiotic treatment significantly reduced the diversity and richness of the gut microbiota of mice. Compared to vehicle-treated mice, antibiotic-treated mice showed reductions in acute itch behavior induced by compound 48/80, chloroquine (CQ), and serotonin (5-HT), respectively. Moreover, repositioning of microbiota reversed the reductions in acute itch behavior in antibiotic-treated mice. In addition, immunofluorescence staining revealed that antibiotic-treated mice displayed decreased c-Fos expression in ipsilateral TG compared to controls. ConclusionsOur study, for the first time, discovered that antibiotic-induced gut microbiota depletion could reduce acute itch behavior, which may be connected with decreased TG neuronal activity.

Melatonin attenuates acute and chronic itch in mice: the antioxidant and anti-inflammatory effects of melatonin receptors.

BackgroundItch is a common symptom of skin diseases and significantly reduces patients’ quality of life. Melatonin has anti-inflammatory and antioxidant effects. Our study examined the potential anti-itch effects of melatonin (N-acetyl-5-methoxytryptamine) in mice.MethodsWe detected the effects of melatonin and its receptors on acute and chronic itch by conducting itching behavioral experiments in male C57 mice. Reactive oxygen species (ROS) levels and calcium ion (Ca2+) mobilization during acute itching production were explored using flow cytometry and calcium imaging techniques. Melatonin expression in the serum of the chronic itch model mice was determined by enzyme-linked immunoassays. Hematoxylin and eosin staining show the effects of melatonin on skin thickness in a chronic itch model. Cytokine and chemokine levels were determined by quantitative polymerase chain reaction.ResultsWe discovered that compound 48/80 (C48/80)- and chloroquine (CQ)-induced scratching were significantly decreased by intraperitoneal (i.p), intradermal, and intrathecal administration of melatonin in a dose-dependent manner in mice, and the co-administration of melatonin receptor antagonists abolished the anti-itch effects of i.d melatonin. The incubation of melatonin significantly decreased the intracellular ROS levels induced by C48/80 and CQ in cultured ND7/23 cells from a mouse x rat hybridoma nerve as neuron. Melatonin inhibited intracellular Ca2+ increases induced by CQ (but not C48/80) in cultured dorsal root ganglia (DRG) neurons. Melatonin (50 mg/kg i.p) attenuated imiquimod (IMQ)- or acetone and diethyl ether followed by acetone-ether-water (AEW)-induced chronic itch and epidermal hyperplasia in mice. Finally, melatonin treatment reduced the IMQ-induced expression of ST2 and interleukin-33 (IL-33) or the AEW-induced expression of interleukin 31 (IL-31) and interleukin 31 receptor A (IL-31 RA) in the mice.ConclusionsCollectively, our results indicate that melatonin attenuates acute and chronic itch, possibly via melatonin receptors, and its antioxidant, and anti-inflammatory effects in mice.

Miswiring of Merkel cell and pruriceptive C fiber drives the itch-scratch cycle.

Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3+ pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.

Molecular Determinants of Mechanical Itch Sensitization in Chronic Itch.

Chronic itch is associated with sensitization of the somatosensory nervous system. Recent studies have identified the neural circuits transmitting acute itch; however, the mechanisms by which itch transforms into a pathological state remain largely unknown. We have previously shown that Aβ low-threshold mechanoreceptors, together with spinal urocortin 3-positive (Ucn3+) excitatory interneurons and neuropeptide Y-positive (NPY+) inhibitory interneurons, form a microcircuit that transmits and gates acute mechanical itch. Here, using whole-cell patch-clamp recordings, we observed increased excitability in spinal Ucn3+ neurons under chronic itch conditions. In contrast to Ucn3+ neurons, the excitability of spinal NPY+ neurons was largely reduced under chronic itch conditions. To explore the molecular mechanisms underlying sensitization of this microcircuit, we examined the mRNA expression levels of voltage-gated ion channels in recorded spinal Ucn3+ and NPY+ neurons by single-cell quantitative real-time PCR (qRT-PCR). We found that the expression levels of Nav1.6 and Cav2.3 channels were increased in spinal Ucn3+ neurons in chronic itch mice, while the expression level of SK3 channels was decreased. By contrast, the expression levels of Nav1.6 and BK channels were decreased in spinal NPY+ neurons in chronic itch mice. To determine the contribution of different ion channels in chronic itch sensitization, we then used a Markov Chain Monte Carlo method to parameterize a large number of biophysically distinct multicompartment models of Ucn3+ and NPY+ neurons. These models included explicit representations of the ion channels that we found to be up- or down-regulated under chronic itch conditions. Our models demonstrated that changes in Nav1.6 conductance are predominantly responsible for the changes in excitability of both Ucn3+ and NPY+ neurons during chronic itch pathogenesis. Furthermore, when simulating microcircuits of our Ucn3+ and NPY+ models, we found that reduced Nav1.6 conductance in NPY+ models played a major role in opening the itch gate under chronic itch conditions. However, changing SK, BK, or R-type calcium channel conductance had negligible effects on the sensitization of this circuit. Therefore, our results suggest that Nav1.6 channels may play an essential role in mechanical itch sensitization. The findings presented here may open a new avenue for developing pharmaceutical strategies to treat chronic itch.

The PLAUR signaling promotes chronic pruritus.

Chronic itch is a complex sensation of the skin frequently associated with skin diseases, such as atopic dermatitis (AD) and psoriasis. Although Serpin E1 is implicated in chronic itch, its receptor and signaling pathways involved in itch are not known. In this study, the clinical relevance of a putative Serpin E1 receptor PLAUR to chronic itch, and the neuro‐cutaneous Serpin E1‐PLAUR signaling are explored. We found that PLAUR is overexpressed in skin specimens of human lesional AD and lesional psoriasis, and sensory neurons innervating MC903‐induced AD‐like murine skin. Murine PLAUR+ sensory neurons responded to Serpin E1, resulting in enrichment of numerous itch‐ and inflammation‐related genes and their protein release. PLAUR resides in TLR2+ neurons and Serpin E1 stimulus led to transcriptional upregulation of TLR2 and its co‐signaling proteins. Agonists of TLR2 propagated itch‐related gene transcription including BNP, OSM, and PAR2. OSM induced acute itch in mice and promoted G‐CSF and IL‐8 release from human keratinocytes. Serpin E1 inhibitor reduced MC903‐induced itch, epidermal hyperplasia, immunocyte infiltration, and resulted in lower transcription/expression levels of Serpin E1 and OSM. Taken together, the PLAUR‐TLR2‐OSM signaling promotes skin‐nerve communication, cutaneous inflammation, and itch, all feeding into an aggravation of AD and exaggerated itch circuits.

Prevalence of Itch in German Schoolchildren: A Population-based Study.

Itch is a common symptom, but there is limited evidence on the prevalence of itch in children. The aim of this study was to assess the prevalence of itch in schoolchildren. A questionnaire was developed by experts in the field and based on a literature search. The questionnaire was applied in a pilot study of 25 consecutively selected paediatric patients and their parents. It confirmed the high content validity of the questionnaire, and the questionnaire was comparable to hospital records regarding chronic itch (n = 19, mean consistency 89.47%). The questionnaire was distributed among German schoolchildren in 9/12 randomly selected primary schools in Kiel, Germany. Of 1,722 invited students, 443 schoolchildren aged 6–10 years participated, and 26.2% (n = 116) reported itch. The prevalence of acute itch was 20.0% (n = 87), and 14.7% (n = 65) reported chronic itch. Reduced sleep and mood were often related to chronic itch. This study demonstrated that itch is a common symptom in German schoolchildren.

Topical Capsaicin in Poly(lactic-co-glycolic)acid (PLGA) Nanoparticles Decreases Acute Itch and Heat Pain.

Background: Capsaicin, the hot pepper agent, produces burning followed by desensitization. To treat localized itch or pain with minimal burning, low capsaicin concentrations can be repeatedly applied. We hypothesized that alternatively controlled release of capsaicin from poly(lactic-co-glycolic acid) (PLGA) nanoparticles desensitizes superficially terminating nociceptors, reducing burning. Methods: Capsaicin-loaded PLGA nanoparticles were prepared (single-emulsion solvent evaporation) and characterized (size, morphology, capsaicin loading, encapsulation efficiency, in vitro release profile). Capsaicin-PLGA nanoparticles were applied to murine skin and evaluated in healthy human participants (n = 21) for 4 days under blinded conditions, and itch and nociceptive sensations evoked by mechanical, heat stimuli and pruritogens cowhage, β-alanine, BAM8-22 and histamine were evaluated. Results: Nanoparticles (loading: 58 µg capsaicin/mg) released in vitro 23% capsaicin within the first hour and had complete release at 72 h. In mice, 24 h post-application Capsaicin-PLGA nanoparticles penetrated the dermis and led to decreased nociceptive behavioral responses to heat and mechanical stimulation (desensitization). Application in humans produced a weak to moderate burning, dissipating after 3 h. A loss of heat pain up to 2 weeks was observed. After capsaicin nanoparticles, itch and nociceptive sensations were reduced in response to pruritogens cowhage, β-alanine or BAM8-22, but were normal to histamine. Conclusions: Capsaicin nanoparticles could be useful in reducing pain and itch associated with pruritic diseases that are histamine-independent.

Sensory neuron-expressed TRPC3 mediates acute and chronic itch.

Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represents a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in most presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-like and pain-like behaviors in naive mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of contact hypersensitivity (CHS), the Trpc3 mRNA expression level and function were upregulated in the TG after CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch through a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.

IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL‐20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL‐20 in AD remains unknown. Here, RNA‐seq, Q‐PCR, and immunocytochemistry were utilized to examine disease‐driven changes of IL‐20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD‐models. Calcium imaging, knockdown and cytokine array were used to investigate IL‐20‐evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL‐20‐elicited sensations in vivo. We found that transcripts and protein of IL‐20 were upregulated in skin from human AD and murine AD‐like models. Topical MC903 treatment in mice ear enhanced IL‐20R1 expression in the trigeminal sensory ganglia, suggesting a lesion‐associated and epidermal‐driven mechanism for sensitization of sensory IL‐20 signaling. IL‐20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD‐related molecule release and transcription of itch‐related genes. In sensory neurons, IL‐20 application increased TLR2 transcripts, implicating a link between innate immune response and IL‐20. In a murine cheek model of acute itch, intradermal injection IL‐20 and IL‐13 elicited significant itch‐like behavior, though only when co‐injected. Our findings provide novel insights into IL‐20 function in peripheral (skin‐derived) itch and clinically relevant intercellular neuron‐epidermal communication, highlighting a role of IL‐20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL‐20 epidermal pathways.