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Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

At our body surface, the epidermis absorbs UV radiation. UV overexposure leads to sunburn with tissue injury and pain. To understand how, we focus on TRPV4, a nonselective cation channel highly expressed in epithelial skin cells and known to function in sensory transduction, a property shared with other transient receptor potential channels. We show that following UVB exposure mice with induced Trpv4 deletions, specifically in keratinocytes, are less sensitive to noxious thermal and mechanical stimuli than control animals. Exploring the mechanism, we find that epidermal TRPV4 orchestrates UVB-evoked skin tissue damage and increased expression of the proalgesic/algogenic mediator endothelin-1. In culture, UVB causes a direct, TRPV4-dependent Ca ²⁺ response in keratinocytes. In mice, topical treatment with a TRPV4-selective inhibitor decreases UVB-evoked pain behavior, epidermal tissue damage, and endothelin-1 expression. In humans, sunburn enhances epidermal expression of TRPV4 and endothelin-1, underscoring the potential of keratinocyte-derived TRPV4 as a therapeutic target for UVB-induced sunburn, in particular pain.

Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. However, understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models. We used a recently established mouse model with epidermal overexpression of PAR2 (PAR2OE) and littermate WT mice to study the impact of increased PAR2 expression in epidermal cells on spontaneous and house dust mite (HDM)-induced skin inflammation, itch, and barrier dysfunction in AD, and . PAR2OE newborns displayed no overt abnormalities, but spontaneously developed dry skin, severe pruritus, and eczema. Dermatological, neurophysiological, and immunological analyses revealed the hallmarks of AD-like skin disease. Skin barrier defects were observed before onset of skin lesions. Application of HDM onto PAR2OE mice triggered pruritus and the skin phenotype. PAR2OE mice displayed an increased density of nerve fibers, increased nerve growth factor and endothelin-1 expression levels, alloknesis, enhanced scratching (hyperknesis), and responses of dorsal root ganglion cells to non-histaminergic pruritogens. PAR2 in keratinocytes, activated by exogenous and endogenous proteases, is sufficient to drive barrier dysfunction, inflammation, and pruritus and sensitize skin to the effects of HDM in a mouse model that mimics human AD. PAR2 signaling in keratinocytes appears to be sufficient to drive several levels of neuro-epidermal communication, another feature of human AD.

Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

The autoimmune hair loss disorder alopecia areata (AA), is characterized by immune privilege (IP) collapse of the hair follicle (HF) bulb resulting from a Th1-dependent inflammatory response. Although CD8 + T cells are recognized key drivers of the disease, it remains to be clarified whether the activation of HF resident T cells suffice to initiate IP loss and thus elicit the cascade of events leading to AA. Here, we utilized the human microdissected HF organ culture model to answer this question by activating intra- and peri-follicular HF resident T cells with αCD3/αCD28 antibodies. TCR stimulation indeed resulted in enhanced resident T cell proliferation, as indicated by significantly increased CD3 + Ki-67 + cells, and higher intrafollicular CD3 + T cell numbers. Furthermore, αCD3/αCD28 stimulation promoted key signs of HF IP collapse, by increasing bulbar MHC class I and II expression and elevating MHC class II + cells numbers. We next sought to investigate whether T cell proliferation plays a central role in the TCR activation–dependent collapse of the bulb IP. To test this, we co-administered the DHODH inhibitor farudodstat 1 day prior and during the stimulation with αCD3/αCD28 in HF organ culture. Short-term treatment with farudodstat reduced the increase in T cell proliferation and significantly decreased the upregulated MHC class I and II expression induced by TCR stimulation with αCD3/αCD28. Our results show that stimulation of HF resident T cells via TCR engagement induces an AA–like phenotype in healthy human HFs ex vivo , characterized by T cell proliferation and subsequent IP collapse. DHODH inhibition with farudodstat only partially reduces T cell numbers but prevented HF IP collapse induction.

IL-33 is a newly recognized cytokine of the IL-1 cytokine family that has recently been attributed to the epithelial “alarmin” defense system. IL-33 is released by the epithelial cells in various tissues and organs, including keratinocytes, endothelial cells, and immune cells. Recent reports have suggested that IL-33 might be a critical part of the innate immunity, although its precise role is as yet poorly understood. In several organs, IL-33 appears to drive T helper type 2 (Th2) responses, suggesting roles in allergic and atopic diseases, as well as in fibrosis. IL-33 exerts its effects by activating the ST2 (suppression of tumorigenicity 2)/IL-1 aR receptor on different types of cells, including mast cells and Th2 cells. The ST2 receptor is either expressed on the cell surface or shed from these cells (soluble ST2, sST2), thereby functioning as a “decoy” receptor. After binding to its receptor, IL-33 activates NF-κB, suggesting that it regulates the outcome of diseases such as atopic dermatitis. On the other hand, several studies have reported on the inhibitory effects of sST2 in inflammatory and fibrotic diseases, suggesting that IL-33/ST2 is a unique cytokine with potential pro- and anti-inflammatory effects.

Introduction Eblasakimab, a first-in-class monoclonal antibody with a unique mechanism to target the interleukin (IL)-13 receptor alpha 1 (IL-13Rα1), inhibits IL-4/IL-13 signaling in the pathophysiology of atopic dermatitis (AD). This study investigates the impact of eblasakimab on type 2 inflammatory biomarkers in patients with moderate-to-severe AD. Methods A double‑blind, multiple ascending dose, phase Ib study evaluated the effect of eblasakimab (200, 400, 600 mg) or placebo administered subcutaneously once weekly for 8 weeks in patients with moderate‑to‑severe AD. Serum levels of thymus and activation-regulated chemokine (TARC), total immunoglobulin E (IgE), and lactate dehydrogenase (LDH) were assessed. Results Eblasakimab suppressed TARC, IgE, and LDH in the 400-mg and 600-mg groups over 8 weeks of treatment. Patients in the 400-mg and 600-mg groups experienced a reduction of 72.8% ( p  = 0.004) and 62.9% ( p  = 0.003), respectively, for TARC, 35.1% ( p  = 0.006) and 20.9% (not significant; NS), respectively, for IgE, and 24.6% (NS) and 23.1% (NS), respectively, for LDH between baseline and Week 8. Reduction in serum TARC in the 400-mg group was significantly greater than placebo as early as Week 1, whereas reductions in total IgE were more gradual. Serum TARC and total IgE remained suppressed in the 400-mg and 600-mg eblasakimab groups for 4–6 weeks following the last administered dose. Conclusion The effect of eblasakimab on circulating AD‑associated biomarker levels was accompanied by improvements in signs and symptoms of AD, consistent with the inhibition of IL-13 and IL-4 signaling via the type 2 receptor. Trial Registration Number NCT04090229.

Lightly touching normal skin near a site of itch can elicit itch sensation, a phenomenon known as alloknesis. To investigate the neural mechanisms of alloknesis, we have developed an animal model. Low-threshold mechanical stimulation of the skin normally does not elicit any response in naive C57/BL6 mice. Following acute intradermal (i.d.) injection of histamine in the rostral back, mechanical stimulation 7mm from the injection site elicited discrete hindlimb scratch bouts directed toward the stimulus. This began at 10minutes and peaked 20–40minutes post histamine injection, declining over the next hour. Histamine itself elicited bouts of scratching not associated with the mechanical stimulus, which ceased after 30minutes. Histamine- and touch-evoked scratching was inhibited by the μ-opiate antagonist naltrexone. Touch-evoked scratching was observed following i.d. 5-HT (5-hydroxytryptamine), a protease-activated receptor (PAR)-4 agonist, and an MrgprC11 agonist BAM8-22, but not chloroquine or a PAR-2 agonist. The histamine H1 receptor antagonist terfenadine prevented scratching and alloknesis evoked by histamine, but not 5-HT, a PAR-4 agonist or an MrgprC11 agonist. In mice with experimental dry skin, there was a time-dependent increase in spontaneous and touch-evoked scratching. This animal model appears to be useful to investigate neural mechanisms of itch and alloknesis.

Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.