Anti-pruritic Effect of Isothiocyanates: Potential Involvement of Toll-like Receptor 3 Signaling

Overview

Journal Pharmacol Res Perspect

Date 2022 Dec 12

PMID 36507603

Authors

Masaki Moriyama

Mitsuhiro Konno

Kanako Serizawa

Natsumi Yuzawa

Yuki Majima

Ikuo Hayashi

Tomohiko Suzuki

Mie Kainoh

Affiliations

Soon will be listed here.

Abstract

The innate immune system has an emerging role as a mediator of neuro-immune communication and a therapeutic target for itch. Toll-like receptor 3 (TLR3) plays an important role in itch, as shown in TLR3 knock-out mice. In this study, to evaluate effects of TLR3 inhibitors on histamine-independent itch, we used two kinds of isothiocyanate (ITC). Both phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) inhibited Poly I:C (PIC)-induced signaling in the RAW264.7 cell line. We then investigated the anti-pruritic effect of these compounds on PIC- and chloroquine (CQ)-induced scratching behavior. PEITC and SFN both suppressed PIC-evoked scratching behavior in mice, and PEITC also inhibited CQ-induced acute itch. Finally, we examined the oxazolone-induced chronic itch model in mice. Surprisingly, oral dosing of both compounds suppressed scratching behaviors that were observed in mice. Our findings demonstrate that TLR3 is a critical mediator in acute and chronic itch transduction in mice and may be a promising therapeutic target for pruritus in human skin disorders. It is noteworthy that SFN has potential for use as an antipruritic as it is a phytochemical that is used as a supplement.

Citing Articles

Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane.

Habtemariam S Biomedicines. 2024; 12(6).

PMID: 38927376 PMC: 11200786. DOI: 10.3390/biomedicines12061169.

Anti-pruritic effect of isothiocyanates: Potential involvement of toll-like receptor 3 signaling.

Moriyama M, Konno M, Serizawa K, Yuzawa N, Majima Y, Hayashi I Pharmacol Res Perspect. 2022; 10(6):e01038.

PMID: 36507603 PMC: 9741980. DOI: 10.1002/prp2.1038.

References

Rundle C, Dellavalle R . PatientsLikeMe and atopic dermatitis: characterizing the atopic dermatitis patient profile. Dermatol Online J. 2019; 24(8). View

Nakamura N, Tamagawa-Mineoka R, Ueta M, Konishi E, Yasuike R, Masuda K . Stratum corneum Toll-like receptor 3 expressions correlate with the severity of atopic dermatitis lesions. J Dermatol Sci. 2019; 94(3):354-357. DOI: 10.1016/j.jdermsci.2019.05.005. View

Wadachi R, Hargreaves K . Trigeminal nociceptors express TLR-4 and CD14: a mechanism for pain due to infection. J Dent Res. 2005; 85(1):49-53. PMC: 2227946. DOI: 10.1177/154405910608500108. View

Silverberg N . Atopic dermatitis prevention and treatment. Cutis. 2017; 100(3):173. View

Park H, Kim S, Park S, Eom S, Gu G, Kim S . Phenethyl isothiocyanate regulates inflammation through suppression of the TRIF-dependent signaling pathway of Toll-like receptors. Life Sci. 2013; 92(13):793-8. DOI: 10.1016/j.lfs.2013.02.012. View

Carstens E, Follansbee T, Carstens M . The Challenge of Basic Itch Research. Acta Derm Venereol. 2020; 100(2):adv00023. PMC: 7295076. DOI: 10.2340/00015555-3343. View

Jaafaru M, Abd Karim N, Enas M, Rollin P, Mazzon E, Razis A . Protective Effect of Glucosinolates Hydrolytic Products in Neurodegenerative Diseases (NDDs). Nutrients. 2018; 10(5). PMC: 5986460. DOI: 10.3390/nu10050580. View

Schepici G, Bramanti P, Mazzon E . Efficacy of Sulforaphane in Neurodegenerative Diseases. Int J Mol Sci. 2020; 21(22). PMC: 7698208. DOI: 10.3390/ijms21228637. View

Usoskin D, Furlan A, Islam S, Abdo H, Lonnerberg P, Lou D . Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 2014; 18(1):145-53. DOI: 10.1038/nn.3881. View

10.

Moriyama M, Konno M, Serizawa K, Yuzawa N, Majima Y, Hayashi I . Anti-pruritic effect of isothiocyanates: Potential involvement of toll-like receptor 3 signaling. Pharmacol Res Perspect. 2022; 10(6):e01038. PMC: 9741980. DOI: 10.1002/prp2.1038. View

11.

Meng J, Steinhoff M . Molecular mechanisms of pruritus. Curr Res Transl Med. 2016; 64(4):203-206. DOI: 10.1016/j.retram.2016.08.006. View

12.

Nowicki D, Krause K, Szamborska P, Zukowska A, Cech G, Szalewska-Palasz A . Induction of the Stringent Response Underlies the Antimicrobial Action of Aliphatic Isothiocyanates. Front Microbiol. 2021; 11:591802. PMC: 7874123. DOI: 10.3389/fmicb.2020.591802. View

13.

Steinhoff M, Oaklander A, Szabo I, Stander S, Schmelz M . Neuropathic itch. Pain. 2019; 160 Suppl 1:S11-S16. DOI: 10.1097/j.pain.0000000000001551. View

14.

Mastuo T, Miyata Y, Yuno T, Mukae Y, Otsubo A, Mitsunari K . Molecular Mechanisms of the Anti-Cancer Effects of Isothiocyanates from Cruciferous Vegetables in Bladder Cancer. Molecules. 2020; 25(3). PMC: 7037050. DOI: 10.3390/molecules25030575. View

15.

Yosipovitch G, Rosen J, Hashimoto T . Itch: From mechanism to (novel) therapeutic approaches. J Allergy Clin Immunol. 2018; 142(5):1375-1390. DOI: 10.1016/j.jaci.2018.09.005. View

16.

Shiratori-Hayashi M, Koga K, Tozaki-Saitoh H, Kohro Y, Toyonaga H, Yamaguchi C . STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat Med. 2015; 21(8):927-31. DOI: 10.1038/nm.3912. View

17.

Takano N, Arai I, Kurachi M . Analysis of the spontaneous scratching behavior by NC/Nga mice: a possible approach to evaluate antipruritics for subjects with atopic dermatitis. Eur J Pharmacol. 2003; 471(3):223-8. DOI: 10.1016/s0014-2999(03)01828-4. View

18.

Liu T, Berta T, Xu Z, Park C, Zhang L, Lu N . TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest. 2012; 122(6):2195-207. PMC: 3366391. DOI: 10.1172/JCI45414. View

19.

Gooderham M, Hong H, Eshtiaghi P, Papp K . Dupilumab: A review of its use in the treatment of atopic dermatitis. J Am Acad Dermatol. 2018; 78(3 Suppl 1):S28-S36. DOI: 10.1016/j.jaad.2017.12.022. View

20.

Szollosi A, McDonald I, Szabo I, Meng J, van den Bogaard E, Steinhoff M . TLR3 in Chronic Human Itch: A Keratinocyte-Associated Mechanism of Peripheral Itch Sensitization. J Invest Dermatol. 2019; 139(11):2393-2396.e6. DOI: 10.1016/j.jid.2019.04.018. View