Novel insights into the TRPV3mediated itch in atopic dermatitisTo the Editor:Chronic pruritus (itch) is a widespread and debilitating condition associated with dermatologic, systemic, neuropathic, or psychogenic disorders. The pathophysiologic mechanisms underpinning the transduction and potentiation of this refractory pruritus remain unclear. Current therapeutics are largely ineffective. 1 Thus, we have aimed to address this gap in knowledge by specifically focusing on clinically relevant intercellular communication in human skin cells, murine models of acute and chronic itch, and samples from human atopic dermatitis (AD) and psoriasis.In conditions of chronic dermatologic itch such as AD and psoriasis, certain members of the transient receptor potential (TRP) ion channel superfamily play an important role in the propagation of itch signaling. TRP vanilloid channel 3 (TRPV3) is a calcium-permeable cation channel that is abundantly expressed in epidermal keratinocytes. TRPV3 detects warm temperatures (>338C), is gated by a wide range of chemical stimuli, and plays an essential role in skin homeostasis and repair. Heatinduced activation of TRPV3 stimulates the release of a potent itch inducer, thymic stromal lymphopoietin (TSLP), from cultured murine keratinocytes. 2 In mice, intradermal injection of carvacrol, a TRPV3 agonist, elicits scratching behaviors. Gain-of-function mutations in TRPV3 have been confirmed in Olmsted syndrome, a rare pruritic genodermatosis in humans 3 and associated with AD-like inflammation in rodents. TRPV3 is upregulated in the skin of patients with AD. 2 Despite this, much remains unknown about the clinical relevance of TRPV3-linked pathways in human dermatitis and pruritus.Herein, real-time PCR was used to quantify TRPV3 expression in the skin of AD-like protease-activated receptor 2 (PAR2)overexpressing mouse (Grhl3PAR2 /1 mice). The level of TRPV3 transcripts was significantly increased in lesional skin of Grhl3PAR2 /1 mice versus in age-matched wild-type controls (Fig 1, A). Moreover, relative TRPV3 levels were significantly higher in lesional skin of Grhl3PAR2 /1 mice than in nonlesional Grhl3PAR2/ 1 mice (Fig 1, A), suggesting that TRPV3 expression is associated with the severity of dermatitis.Human skin samples were then examined to evaluate the clinical relevance of these murine findings. Specimens were collected from patients with AD (both lesional AD [LAD] and nonlesional AD [NLAD]), from patients with psoriasis (both lesional psoriasis [LPS] and nonlesional psoriasis [NLPS]), and from healthy controls (HC). All were analyzed by RNA sequencing, with data indicating the mean change in transcript level relative to HC. In LAD samples, TRPV3 was the only member of the TRPV family to be upregulated, with transcripts showing greater than a 2-fold increase over the HC levels (Fig 1, B). Similar to our murine model, this upregulation was absent in NLAD skin (Fig 1, C). Levels of TRPV3 transcripts were also increased in LPS skin samples versus in HC skin samples, but not in NLPS sample...

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.

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