PAR2 Pepducin-Based Suppression of Inflammation and Itch in Atopic Dermatitis Models

Barr, Travis P.; Garzia, Chris; Guha, Srijoy; Fletcher, Elizabeth K.; Nguyen, Nga; Wieschhaus, Adam J.; Ferrer, Lluís; Covic, Lidija; Kuliopulos, Athan

doi:10.1016/j.jid.2018.08.019

Cited by 59 publications

(60 citation statements)

References 60 publications

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“…The finding that PAR2 acts upstream of TRPV3 is consistent with a recent in vitro study showing that attenuated TRPV3 function compromised the response of PAR2 to an agonist in keratinocytes (Park et al, 2017). Together with previous studies supporting the roles of PAR2 and TRPV3, independently of one another, in AD (Barr et al, 2019;Yoshioka et al, 2009Yoshioka et al, , 2006, this study provides a causal link between PAR2 and TRPV3 in acute itch as well as chronic pruritus associated with AD. The observation that TRPV3 antagonist 74a attenuated PAR2induced intracellular Ca 2þ responses in mouse and human keratinocytes implies that the function of TRPV3 signaling in itch transmission relies at least in part on the presence of PAR2 in keratinocytes.…”

Section: Discussionsupporting

confidence: 90%

“…Our data taken together suggest that the canonical G q/11 -protein coupled phospholipase C-Ca 2þ signaling pathway is engaged in SLIGRL-induced PAR2 activation in mouse keratinocytes, followed by Ca 2þ mobilization from the endoplasmic reticulum to activate TRPV3, followed by TSLP release in inflammatory skin disease conditions (Figure 5k). Therapeutically, TRPV3 or PAR2 can be either individually or concurrently inhibited to attenuate the allergic inflammation and AD-associated pruritus together (Barr et al, 2019;Nakajima et al, 2014), and such inhibition could target skin exclusively or dampen neuroinflammation, such as decreasing leukocyte recruitment via their targets in other tissues. The PAR2-TRV3 signaling interface may also be an AD-associated itch-specific axis for future exploration of therapeutic strategies for treating AD.…”

Section: Discussionmentioning

confidence: 99%

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PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes

Zhao

Munanairi

Liu

et al. 2020

Journal of Investigative Dermatology

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Animal studies have suggested that transient receptor potential ion channels and G-protein coupled receptors play important roles in itch transmission. TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome, which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of proteaseactivated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis, whereas their inhibition attenuated scratching and inflammatory responses in mouse atopic dermatitis models. These results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in atopic dermatitis.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes

Zhao

Munanairi

Liu

et al. 2020

Journal of Investigative Dermatology

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“…PAR-2, which is highly implicated in itch sensation, is a direct target for several novel anti-itch therapeutics currently under development. The pepducin, PZ-235 significantly reduced the PAR-2-mediated expression of the proinflammatory nuclear factor-κB, thymic stromal lymphopoietin, tumour necrosis factor-α and the differentiation marker K-10 in human keratinocytes by 94-98% (115).…”

Section: Novel Targets For Topical Treatments and Ingredientsmentioning

confidence: 96%

Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions

Yosipovitch¹,

Miséry²,

Proksch³

et al. 2019

Acta Derm Venereol

118

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Itch is a common symptom of many skin barrier-related dermatoses and can severely impact quality of life. However, there are a limited number of effective anti-itch topical therapies currently available and several unmet needs not addressed by current itch management strategies. As our knowledge of the mechanisms underlying itch has improved, several novel therapies have recently emerged that can be incorporated into existing regimens to enhance itch therapy and management. Here, we summarise research and current opinion on available topical therapies and give recommendations for the optimal management of itch. Barrier damage, dry skin and itch are intricately linked and form the basis of many common skin diseases. Damage from environmental insults, or genetic or inflammatory causes, can impair the skin barrier, resulting in an increase in transepidermal water loss and activation of itch-associated nerve fibres. The itch-scratch cycle can perpetuate skin barrier damage and itch. Topical therapeutic strategies are utilised to overcome dry skin and itch, primarily in the form of emollients. Recent advances in our understanding of the mechanisms underlying itch have enabled the development of new topical therapies, which may be incorporated into existing treatment regimes. Ultimately, treatment of dry skin and itch must be highly tailored to the individual according to their needs.

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“…Additionally, experimental evidence points towards the growing importance of certain itch-associated signaling pathways that may be targeted in the near future, including the spinal α2/α3 GABA A receptors, bovine adrenal medulla (BAM) 8-22 and the Mrgpr, sodium channels (Na V 1.7, Na V 1.8, Na V 1.9), natriuretic peptides (BNP) and their receptors (NPR-1), gastrin-releasing peptide receptor (GRPR), PAR2 and CCL2/CCR2 [232][233][234][235][236][237][238][239][240][241][242].…”

Section: Miscellaneous Modalitiesmentioning

confidence: 99%

Emerging Therapeutic Options for Chronic Pruritus

2020

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Chronic pruritus, defined as an unpleasant sensation resulting in a need to scratch that lasts more than 6 weeks, is a prevalent and bothersome symptom associated with both cutaneous and systemic conditions. Due to complex pathogenesis and profuse contributing factors, chronic pruritus therapy remains challenging. Regardless of the well-established antipruritic properties of classic pharmacotherapy (topical therapy, phototherapy and systemic therapy), these methods often provide insufficient relief for affected individuals. Owing to the growing interest in the field of pruritic research, further experimental and clinical data have emerged, continuously supporting the possibility of instigating novel therapeutic measures. This review covers the most relevant current modalities remaining under investigation that possess promising perspectives of approval in the near future, especially opioidergic drugs (mu-opioid antagonists and kappa-opioid agonists), neurokinin-1 receptor antagonists, biologic drugs, Janus kinase inhibitors, ileal bile acid transporter inhibitors, aryl hydrocarbon receptor agonists and histamine H 4 receptor antagonists.

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PAR2 Pepducin-Based Suppression of Inflammation and Itch in Atopic Dermatitis Models

Cited by 59 publications

References 60 publications

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes

Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions

Emerging Therapeutic Options for Chronic Pruritus

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