Enhanced Thermal Sensitivity of TRPV3 in Keratinocytes Underlies Heat-Induced Pruritogen Release and Pruritus in Atopic Dermatitis

Seo, Seong Hoon; Kim, Young Ho; Kim, Song-Ee; Chung, Seungsoo; Lee, Sangeun

doi:10.1016/j.jid.2020.02.028

Cited by 40 publications

(35 citation statements)

References 50 publications

(56 reference statements)

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“…Keratinocyte-derived cytokines, such as TSLP, contributes to the pathogenesis of AD ( Sawada et al, 2019 ). while Keratinocytes from patients with AD show increased level of PGE2 ( Seo et al, 2020 ). DNCB increased the expression level of TSLP in HaCaT cells in an HDAC6-dependent manner ( Figure 7B ).…”

Section: Discussionmentioning

confidence: 99%

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

et al. 2021

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Histone deacetylase 6 (HDAC6) has been known to regulate inflammatory diseases. The role of HDAC6 in allergic skin inflammation has not been studied. We studied the role of HDAC6 in atopic dermatitis (AD) and the mechanisms associated with it. The decreased expression or chemical inhibition of HDAC6 suppressed AD by decreasing autophagic flux and cellular features of AD. AD increased expression levels of the Th1 and Th2 cytokines, but decreased expression levels of forkhead box P3 (FoxP3) and interleukin-10 (IL-10) in an HDAC6-dependent manner. CXC chemokine ligand 13 (CXCL13), which was increased in an HDAC6-depenednt manner, mediated AD. MiR-9, negatively regulated by HDAC6, suppressed AD by directly regulating the expression of sirtuin 1 (SIRT1). The downregulation or inhibition of SIRT1 suppressed AD. Experiments employing culture medium and transwell suggested that cellular interactions involving mast cells, keratinocytes, and dermal fibroblast cells could promote AD; HDAC6 and CXCL13 were found to be necessary for these cellular interactions. Mouse recombinant CXCL13 protein increased HDAC6 expression in skin mast cells and dermal fibroblast cells. CXCL13 protein was found to be present in the exosomes of DNCB-treated skin mast cells. Exosomes of DNCB-treated skin mast cells enhanced invasion potentials of keratinocytes and dermal fibroblast cells and increased expression levels of HDAC6, SIRT1 and CXCL13 in keratinocytes and dermal fibroblast cells. These results indicate that HDAC6 and CXCL13 may serve as targets for the developing anti-atopic drugs.

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Section: Discussionmentioning

confidence: 99%

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

et al. 2021

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“…Keratinocytes isolated from AD patients display enhanced expression and heat sensitivity with hyperactive channel function of TRPV3. Agonists of TRPV3 increased IL-33 production, as well as TSLP, NGF, PGE2, in human keratinocytes and induced scratching behavior upon intradermal injection in mice ( 143 ). Activation of TRPV3 also triggers release of multiple factors, including PGE2, ATP, nitric oxide, and NGF, further contributing to the inflammation processes in dermatitis in skin level ( 144 ).…”

Section: Mechanisms For Th2-promoted Trp Channel Sensitizationmentioning

confidence: 99%

Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis

Meng

Fischer

et al. 2021

Front. Immunol.

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Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.

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“…TRPV3 is responsive to warm temperatures (<33°C) and is predominantly expressed in skin keratinocytes, where it mediates warm and pain sensation ( Peier et al, 2002 ; Smith et al, 2002 ). A study showed that activated TRPV3 increases thymic stromal lymphopoietin (TSLP), nerve growth factor, prostaglandin E2, and interleukin (IL)-33 production in human keratinocytes and induces scratching behavior in mice ( Seo et al, 2020 ). The stimulation of TRPV3 can also trigger a strong proinflammatory response via the NF-κ B pathway ( Szollosi et al, 2018 ).…”

Section: Calcium-sensing Receptors and Channels Mediated Ca 2+ Signaling In Skin Function Maintenancementioning

confidence: 99%

“…Mutations have been identified in the TRPV3 gene, thereby linking TRPV3 to pruritus and AD ( Asakawa et al, 2006 ; Yoshioka et al, 2009 ). TRPV3 is upregulated in the skin of MC903-induced AD mouse model and the pharmacologic inhibition of TRPV3, attenuates production of inflammation factors and scratching behavior induced by AD ( Seo et al, 2020 ), suggesting that TRPV3 may be a potential therapeutic target for AD. TRPV3 knockout mice exhibit curly whiskers and body fur abnormalities ( Cheng et al, 2010 ), while hairless DS-Nh mice also exhibit signs of spontaneous dermatitis, resembling human AD ( Asakawa et al, 2006 ).…”

Section: Dermatological Diseasesmentioning

confidence: 99%

Calcium Channels: Noteworthy Regulators and Therapeutic Targets in Dermatological Diseases

Wang

et al. 2021

Front. Pharmacol.

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Dysfunctional skin barrier and impaired skin homeostasis may lead to or aggravate a series of dermatologic diseases. A large variety of biological events and bioactive molecules are involved in the process of skin wound healing and functional recovery. Calcium ions (Ca2+) released from intracellular stores as well as influx through plasma membrane are essential to skin function. Growing evidence suggests that calcium influx is mainly regulated by calcium-sensing receptors and channels, including voltage-gated, transient potential receptor, store-operated, and receptor-operated calcium channels, which not only maintain cellular Ca2+ homeostasis, but also participate in cell proliferation and skin cell homeostasis through Ca2+-sensitive proteins such as calmodulin (CaM). Furthermore, distinct types of Ca2+ channels not merely work separately, they may work concertedly to regulate cell function. In this review, we discussed different calcium-sensing receptors and channels, including voltage-gated, transient receptor potential, store-operated, and receptor-operated calcium channels, particularly focusing on their regulatory functions and inherent interactions as well as calcium channels-related reagents and drugs, which is expected to bridge basic research and clinical applications in dermatologic diseases.

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Enhanced Thermal Sensitivity of TRPV3 in Keratinocytes Underlies Heat-Induced Pruritogen Release and Pruritus in Atopic Dermatitis

Cited by 40 publications

References 50 publications

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis

Calcium Channels: Noteworthy Regulators and Therapeutic Targets in Dermatological Diseases

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