Glucosylsphingosine evokes pruritus via activation of 5-HT2A receptor and TRPV4 in sensory neurons.
A proposed signalling pathway for Gluocosylsphingosine(GS)-evoked pruritus. The highly accumulated GS in the epidermis of patients with AD will activate the peripheral sensory neuron to induce pruritus in the following way: (1) GS activates 5-HT2A receptor (5-HT2A) with subsequent stimulation of PLC via Gαq/11 and Gβγ complex, which in turn breaks down phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). DAG will then activate phosphokinase C (PKC), which leads to sensitization of TRPV4. (2) Activation of the sensitized TRPV4 can be directly facilitated by GS, which will allow a massive influx of cations from the extracellular regions, increasing a chance to induce depolarization and possibly an action potential. This GS-induced electrical signal produced in the peripheral sensory neuron will be further transmitted through the spinal cord and to the brain, where the signal can finally be perceived as pruritus.
Sanjel B, Kim BH, Song MH, Carstens E, Shim WS. Glucosylsphingosine evokes pruritus via activation of 5-HT2A receptor and TRPV4 in sensory neurons. Br J Pharmacol. 2022 May;179(10):2193-2207.
Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus
Summary of the mechanism underlying dry skin-induced pruritus. The production of TSLP in keratinocytes increases under dry skin conditions, in a TRPV4-dependent manner. Additionally, TSLP acts on TSLPR in mast cells to promote the release of tryptase, which in turn stimulates the keratinocytes via PAR2 and TRPV4 to produce more TSLP, thus generating a positive feedback loop of increased TSLP production. TSLP can also act on TSLPR in sensory neurons to transmit electrical signals towards the spinal cord, which are conveyed to the brain and finally perceived as itch.
Lee WJ, Shim WS. Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus. Front Immunol. 2021 Dec 2;12:772941.
Caffeic acid phenethyl ester inhibits pseudo‑allergic reactions via inhibition of MRGPRX2/MrgprB2‑dependent mast cell degranulation
Mast cells play essential role in allergic reactions through the process called mast cell degranulation. Recent studies have found that a basic secretagogue compound 48/80 (C48/80) induces non-IgE-mediated mast cell degranulation via activation of human Mas-related G protein-coupled receptor X2 (MRGPRX2) and mouse MrgprB2. Although previous studies have revealed that caffeic acid (CA) and its derivatives possess anti-allergic effects via IgE-dependent manner, it is largely elusive whether these compounds have impact on MRGPRX2/MrgprB2 to exert inhibitory effects. Therefore, the present study investigated whether CA as well as its derivatives – rosmarinic acid (RA) and caffeic acid phenethyl ester (CAPE) – has the ability to inhibit the activity of MRGPRX2/MrgprB2 to evoke pseudo-allergic effects. As a result, it was found that CAPE inhibits C48/80-induced activation of MRGPRX2/MrgprB2, but neither CA nor RA showed discernible inhibition. Furthermore, the β-hexosaminidase release assay showed that CAPE inhibits mouse peritoneal mast cell degranulation in both IgE-dependent and MrgprB2-dependent manners. Additionally, mouse paw edema induced by C48/80 was dramatically suppressed by co-treatment of CAPE, suggesting that CAPE possesses a protective effect on C48/80-evoked pseudo-allergic reactions. The pretreatment of CAPE also significantly decreased scratching bouts of mice evoked by C48/80, demonstrating that CAPE also has an anti-pruritic effect. Therefore, these data implicate that CAPE can suppress pseudo-allergic reactions evoked by C48/80 via MrgprB2-dependent manner. Finally, molecular docking analysis showed that CAPE is predicted to bind to human MRGPRX2 in the region where C48/80 also binds, implying that CAPE can be a competitive inhibitor of MRGPRX2. In conclusion, it is found that CAPE has the ability to inhibit MRGPRX2/MrgprB2, leading to the prevention of mast cell degranulation and further to the alleviation of mast cell reactions. These results indicate that CAPE as a CA derivative could be developed as a new protective agent that exerts dual inhibition of mast cell degranulation mediated by IgE and MRGPRX2/MrgprB2.
Adhikari N, Shim WS. Caffeic acid phenethyl ester inhibits pseudo-allergic reactions via inhibition of MRGPRX2/MrgprB2-dependent mast cell degranulation. Arch Pharm Res. 2022 Sep;45(9):644-657