Clarithromycin-treated chronic spontaneous urticaria with the negative regulation of FcεRΙ and MRGPRX2 activation via CD300f

Delu Che ¹, Tao Zhang ², Tianxiao Zhang ³, Yi Zheng ⁴, Yajing Hou ², Songmei Geng ⁵, Langchong He ⁶

Affiliations Expand

• PMID: 35853276
• DOI: 10.1016/j.intimp.2022.109063

Abstract

Mast cells (MCs) are main effector cells in chronic spontaneous urticaria (CSU). Both Fc epsilon RI (FcεRΙ)- and MAS-related G coupled receptor-X2 (MRGPRX2)-mediated MC activations affect CSU course. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) has been shown to regulate FcεRΙ activation. However, no study has verified CD300f is a target to cure CSU. Therefore this study aimed to verify whether clarithromycin (CLA) regulates FcεRΙ- and MRGPRX2-mediated MC activations via CD300f and shows therapeutic effect on CSU. The target of CLA was verification. CLA inhibited FcεRΙ- and MRGPRX2-mediated MC activations were shown in vivo and in vitro. A single-center, self-comparison study was performed, and CLA-treated CSU was investigated in 28 patients who were not sensitive to the third-generation antihistamines. Serum inflammatory mediators in patients before and after CLA administration were analyzed. CLA effectively inhibited type Ι anaphylactic reactions and pseudo-allergic reactions in mice. Moreover, CLA inhibited FcεRΙ- and MRGPRX2-mediated MC signaling pathway activation. Regulatory effects of CLA were decreased significantly after CD300f knockdown. CLA effectively alleviated the symptoms of wheal and itch and reduced serum cytokine levels in patients. CLA negatively regulated FcεRΙ- and MRGPRX2-mediated MC activation via CD300f and showed significant therapeutic effect on CSU.

Keywords: Chronic spontaneous urticarial; Clarithromycin; Leukocyte mono-immunoglobulin-like receptor 3; Mast cell; Negatively regulation.

Copyright © 2022 Elsevier B.V. All rights reserved.

iPSC-derived human sensory neurons reveal a subset of TRPV1 antagonists as anti-pruritic compounds

Shermaine Huiping Tay, Jeremy Kah Sheng Pang, Winanto Ng, Chong Yi Ng, Zi Jian Khong, Zheng-Shan Chong, Boon Seng Soh & Shi-Yan Ng 

Scientific Reports volume 14, Article number: 31182 (2024) 

Cite this article

Abstract

Signaling interplay between the histamine 1 receptor (H1R) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in mediating histaminergic itch has been well-established in mammalian models, but whether this is conserved in humans remains to be confirmed due to the difficulties in obtaining human sensory neurons (SNs) for experimentation. Additionally, previously reported species-specific differences in TRPV1 function indicate that use of human SNs is vital for drug candidate screening to have a higher chance of identifying clinically effective TRPV1 antagonists. In this study, we built a histamine-dependent itch model using peripheral SNs derived from human induced pluripotent stem cells (hiPSC-SNs), which provides an accessible source of human SNs for pre-clinical drug screening. We validated channel functionality using immunostaining, calcium imaging, and multielectrode array (MEA) recordings, and confirmed the interdependence of H1R and TRPV1 signalling in human SNs. We further tested the amenability of our model for pre-clinical studies by screening multiple TRPV1 antagonists in parallel, identifying SB366791 as a potent inhibitor of H1R activation and potential candidate for alleviating histaminergic itch. Notably, some of the results using our model corroborated with efficacy and side effect findings from human clinical trials, underscoring the importance of this species-specific platform. Taken together, our results present a robust in vitro human model for histaminergic itch, which can be used to further interrogate the molecular basis of human SN function as well as screen for TRPV1 activity-modifying compounds for a number of clinical indications.

Vitexin promotes the anti-senescence effect via inhibiting JAK2/STAT3 in D-Galactose-induced progeria mice and stress-induced premature senescence

Xiaojuan Han ^ab1, Lu Li ^c1, Jiamei Xie ^a, Qing Lei ^a, Yansong Li ^a, Huan Liu ^a, Haoran Sun ^a, Xiaohua Zhang ^a, Xingchun Gou ^ab

https://doi.org/10.1016/j.ejphar.2024.176865

Abstract

Vitexin is a natural flavonoid glycoside compound extracted from the leaves and seeds of Vitex negundo. It is widely distributed in the leaves and stems of numerous plants and exhibites remarkable anti-tumor, anti-inflammatory, and anti-hypertensive properties. However, whether vitexin presents the anti-aging and senescence prevention effect has not been fully elucidated. The purpose of this study is to investigate the effect of vitexin on progeria mice and cellular senescence, as well as its underlying molecular mechanisms. To generate a premature aging/senescence model in vivo and in vitro, we used D-galactose (D-gal), hydrogen peroxide (H₂O₂), and adriamycin (ADR), respectively. Our findings demonstrated that vitexin potentially delays D-gal-induced progeria mice; similar effects were observed in stress-induced premature senescent fibroblasts in culture. Interestingly, this effect of vitexin is closely correlated with the reduction of the senescence-associated secretory phenotype (SASP) and the inhibition of the SASP-related JAK2/STAT3 pathway. Furthermore, we determined that vitexin meets the pharmacological parameters using the freely available ADMET web tool. Collectively, our findings demonstrate that vitexin possesses anti-senescence and anti-aging properties due to the inhibition of SASP and suppression of JAK2/STAT3 signaling pathway.

KCNQ1 is an essential mediator of the sex-dependent perception of moderate cold temperatures

Aytug K Kiper ¹, Sven Wegner ¹, Aklesso Kadala ², Susanne Rinné ¹, Sven Schütte ¹, Zoltán Winter ², Mirjam A R Bertoune ³, Filip Touska ², Veronika Matschke ⁴, Eva Wrobel ⁵, Anne-Kathrin Streit ¹, Florian Lang ⁶, Constanze Schmidt ⁷, Eric Schulze-Bahr ⁸, Martin K-H Schäfer ³, Jakob Voelkl ⁹, Guiscard Seebohm ^4 8, Katharina Zimmermann ^# 2, Niels Decher ^# 1

Affiliations expand

• PMID: 38857404
• PMCID: PMC11194602
• DOI: 10.1073/pnas.2322475121

Abstract

Low temperatures and cooling agents like menthol induce cold sensation by activating the peripheral cold receptors TRPM8 and TRPA1, cation channels belonging to the TRP channel family, while the reduction of potassium currents provides an additional and/or synergistic mechanism of cold sensation. Despite extensive studies over the past decades to identify the molecular receptors that mediate thermosensation, cold sensation is still not fully understood and many cold-sensitive peripheral neurons do not express the well-established cold sensor TRPM8. We found that the voltage-gated potassium channel KCNQ1 (Kv7.1), which is defective in cardiac LQT1 syndrome, is, in addition to its known function in the heart, a highly relevant and sex-specific sensor of moderately cold temperatures. We found that KCNQ1 is expressed in skin and dorsal root ganglion neurons, is sensitive to menthol and cooling agents, and is highly sensitive to moderately cold temperatures, in a temperature range at which TRPM8 is not thermosensitive. C-fiber recordings from KCNQ1^-/- mice displayed altered action potential firing properties. Strikingly, only male KCNQ1^-/- mice showed substantial deficits in cold avoidance at moderately cold temperatures, with a strength of the phenotype similar to that observed in TRPM8^-/- animals. While sex-dependent differences in thermal sensitivity have been well documented in humans and mice, KCNQ1 is the first gene reported to play a role in sex-specific temperature sensation. Moreover, we propose that KCNQ1, together with TRPM8, is a key instrumentalist that orchestrates the range and intensity of cold sensation.

Allergy. 2024 Mar 13. doi: 10.1111/all.16086. 

RNA-sequencing of paired tape-strips and skin biopsies in atopic dermatitis reveals key differences

Blaine Fritz ¹, Anne-Sofie Halling ², Isabel Díaz-Pinés Cort ¹, Maria Oberländer Christensen ², Amalie Thorsti Møller Rønnstad ², Caroline Meyer Olesen ², Mette Hjorslev Knudgaard ³, Claus Zachariae ^3 4, Steffen Heegaard ⁴, Jacob P Thyssen ^2 4, Thomas Bjarnsholt ^1 5

• PMID: 38477552
• DOI: 10.1111/all.16086

Abstract

Background: Skin tape-strips and biopsies are widely used methods for investigating the skin in atopic dermatitis (AD). Biopsies are more commonly used but can cause scarring and pain, whereas tape-strips are noninvasive but sample less tissue. The study evaluated the performance of skin tape-strips and biopsies for studying AD.

Methods: Whole-transcriptome RNA-sequencing was performed on paired tape-strips and biopsies collected from lesional and non-lesional skin from AD patients (n = 7) and non-AD controls (n = 5). RNA yield, mapping efficiency, and differentially expressed genes (DEGs) for the two methods (tape-strip/biopsy) and presence of AD (AD/non-AD) were compared.

Results: Tape-strips demonstrated a lower RNA yield (22 vs. 4596 ng) and mapping efficiency to known genes (28% vs. 93%) than biopsies. Gene-expression profiles of paired tape-strips and biopsies demonstrated a medium correlation (R² = 0.431). Tape-strips and biopsies demonstrated systematic differences in measured expression levels of 6483 genes across both AD and non-AD samples. Tape-strips preferentially detected many itch (CCL3/CCL4/OSM) and immune-response (CXCL8/IL4/IL5/IL22) genes as well as markers of epidermal dendritic cells (CD1a/CD207), while certain cytokines (IL18/IL37), skin-barrier genes (KRT2/FLG2), and dermal fibroblasts markers (COL1A/COL3A) were preferentially detected by biopsies. Tape-strips identified more DEGs between AD and non-AD (3157 DEGs) then biopsies (44 DEGs). Tape-strips also detected higher levels of bacterial mRNA than biopsies.

Conclusions: This study concludes that tape-strips and biopsies each demonstrate respective advantages for measuring gene-expression changes in AD. Thus, the specific skin layers and genes of interest should be considered before selecting either method.

Keywords: RNA sequencing; atopic dermatitis; biopsies; inflammation; tape-strips.

© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.