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Psoriasis is inflammatory skin disease associated with itch, a troublesome symptom with few therapeutic options. Transient receptor potential channel 4 (TRPC4) is highly expressed in dorsal root ganglia (DRGs). Recently, we have revealed a previously unknown itch signaling in DRG neurons by which TRPC4 mediates itch to serotonergic antidepressants, and demonstrated the antipruritic effect of the TRPC4 inhibitor ML204. However, the role of TRPC4 in acute and chronic itch is still largely unknown. Here, we have characterized the expression of TRPC4 in peptidergic DRG neurons and showed that acute itch induced by serotonin and histamine was attenuated in TRPC4 knockout (TRPC4 KO) mice and mice treated with ML204. We also showed that silencing TRPC4 in DRG and its inhibition by intradermal injections were also effective in decreasing psoriatic itch after repeated applications of imiquimod (IMQ), a preclinical model of psoriasis. Of clinical relevance, intradermal injections of ML204 in psoriasiform skin significantly reversed IMQ-established chronic itch and cutaneous inflammation. Given that TRPC4 is expressed in human DRGs and a specific inhibitor is in clinical trials, our data not only expand our understanding of itch and psoriasis, but also reveal TRPC4 as a potential therapeutic target with considerable translational benefit.
Learn More >Despite the prevalence of psoriasis, the processing of itch in psoriasis and its impact on the central nervous system (CNS) remain unclear.
Learn More >Chronic allergic itch is a common symptom affecting millions of people and animals, but its pathogenesis is not fully explained. Herein, we show that periostin, abundantly expressed in the skin of patients with atopic dermatitis (AD), induces itch in mice, dogs, and monkeys. We identify the integrin αβ3 expressed on a subset of sensory neurons as the periostin receptor. Using pharmacological and genetic approaches, we inhibited the function of neuronal integrin αβ3, which significantly reduces periostin-induced itch in mice. Furthermore, we show that the cytokine TSLP, the application of AD-causing MC903 (calcipotriol), and house dust mites all induce periostin secretion. Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via peripheral sensory neurons, and we characterize the non-canonical functional role of an integrin in itch.
Learn More >The mast cell-nerve unit classically has represented a fundamental neuroimmune axis in the development of itch because of the traditional prominence of histamine as a pruritogen. However, it is appreciated increasingly that most chronic itch disorders are likely nonhistaminergic in nature, provoking the hypothesis that other novel effector itch mechanisms derived from mast cells are important. In this review, we present an overview of classical mast cell biology and put these concepts into the context of recent advances in our understanding of the regulation and function of the mast cell-nerve unit in itch biology.
Learn More >Itch in atopic dermatitis (AD) is aggravated under warm conditions. Transient receptor potential vanilloid 3 (TRPV3), a member of the thermosensitive TRP channels, is activated by innocuous heat and is abundantly expressed in keratinocytes. The potential role of TRPV3 in itch is illustrated in TRPV3 channelopathies of human and mice. However, the role of TRPV3 in heat-induced itch in AD and the underlying mechanisms are unclear. Here we showed that keratinocytes isolated from patients with AD exhibit enhanced expression and heat sensitivity with hyperactive channel function of TRPV3. Heat stimulus induced enhanced secretion of thymic stromal lymphopoietin (TSLP), nerve growth factor (NGF), and prostaglandin E2 (PGE2) by keratinocytes from AD patients via TRPV3 activation. TRPV3 agonists increased TSLP, NGF, PGE2, and IL-33 production in human keratinocytes and induced scratching behavior upon intradermal injection in mice. TRPV3 was upregulated in the skin of MC903-induced AD mouse model. Heat stimulation to MC903-treated mice increased scratching behavior and produced higher levels of TSLP, NGF, PGE2, and IL-33 from epidermis, which were attenuated by pharmacological inhibition of TRPV3. Moreover, neutralization of TSLP reduced heat-evoked scratching in MC903-challenged mice. These results suggest that TRPV3 is a potential therapeutic target for heat-induced itch in AD.
Learn More >Peripheral somatosensory input is modulated in the dorsal spinal cord by a network of excitatory and inhibitory interneurons. PTF1A is a transcription factor essential in dorsal neural tube progenitors for specification of these inhibitory neurons. Thus, mechanisms regulating expression are key for generating neuronal circuits underlying somatosensory behaviors. Mutations targeted to distinct -regulatory elements for in mice, tested the in vivo contribution of each element individually and in combination. Mutations in an autoregulatory enhancer resulted in reduced levels of PTF1A, and reduced numbers of specific dorsal spinal cord inhibitory neurons, particularly those expressing and Although these mutants survive postnatally, at ∼3-5 wk they elicit a severe scratching phenotype. Behaviorally, the mutants have increased sensitivity to itch, but acute sensitivity to other sensory stimuli such as mechanical or thermal pain is unaffected. We demonstrate a requirement for positive transcriptional autoregulatory feedback to attain the level of the neuronal specification factor PTF1A necessary for generating correctly balanced neuronal circuits.
Learn More >Stasis dermatitis (SD) is a common disease in the elderly population, with pruritus being one of the bothersome symptoms. However, there are few therapeutic modalities available for SD-associated itch because little is known about its pathophysiological mechanism. Therefore, we sought to investigate the mediators of itch in SD using an immunofluorescence study on patient lesions focusing on IL-31. Ex vivo stimulation studies using murine peritoneal macrophages were also used to elucidate the pathological mechanisms of IL-31 generation. In SD lesions, dermal infiltrating IL-31(+) cells were increased in number compared to healthy controls, and the majority of IL-31(+) cells were CD68(+) macrophages. The presence of itch in SD was significantly associated with the amount of CD68(+)/IL-31(+) macrophages and CD68(+)/CD163(+) M2 macrophages. The number of CD68(+)/IL-31(+) macrophages was correlated with the number of dermal CCR4(+) Th2 cells, IL-17(+) cells, basophils, substance P(+) cells, and dermal deposition of periostin and hemosiderin. Furthermore, murine peritoneal macrophages expressed an M2 marker arginase-1 and generated IL-31 when stimulated with a combination of substance P, periostin, and red blood cell lysate (representing hemosiderin). IL-31 from macrophages may play a role in itch in SD.
Learn More >Placebo and nocebo effects can influence somatic symptoms such as pain. For itch and other dermatological symptoms these effects have been far less investigated. This review systematically integrates evidence from both animal (mainly rodents) and human trials on placebo and nocebo effects in itch, itch-related symptoms and conditions of the skin and mucous membranes, and related immune outcomes (e.g., histamine). Thirty-one animal studies, and fifty-five human studies (k = 21 healthy participants, k = 34 patients) were included. Overall, studies consistently show that placebo and nocebo effects can be induced by various methods (e.g., suggestions, conditioning and social cues), despite high heterogeneity across studies. Effects of suggestions were found consistently across subjective and behavioral parameters (e.g., itch and scratching in humans), whereas conditioning was likely to impact physiological parameters under certain conditions (e.g., conditioning of histamine levels in stressed rodents). Brain areas responsible for itch processing were associated with nocebo effects. Future research may investigate how variations in methods impact placebo and nocebo effects, and whether all symptoms and conditions can be influenced equally.
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