“Note: Please use the DOI link to access the full article. Unfortunately, due to the file size, I am unable to upload the PDF. I apologize for the inconvenience, and thank you for your understanding.”

A mast cell receptor mediates post-stroke brain inflammation via a dural-brain axis

Ruchita Kothari¹ ∙ Mostafa W. Abdulrahim² ∙ Hyun Jong Oh^1,9 ∙ Daniel H. Capuzzi^1,9 ∙ Collin B. Kilgore¹ ∙ Sumil K. Nair² ∙ Yaowu Zhang² ∙ Nathachit Limjunyawong¹ ∙ Sarbjit S. Saini³ ∙ Jennifer E. Kim⁴ ∙ Justin M. Caplan² ∙ Fernanado L. Gonzalez² ∙ Christopher M. Jackson² ∙ Chetan Bettegowda² ∙ Judy Huang² ∙ Bhanu P. Ganesh⁵ ∙ Chunfeng Tan⁵ ∙ Raymond C. Koehler⁶ ∙ Rafael J. Tamargo² ∙ Louise D. McCullough⁵ ∙ Risheng Xu² rxu4@jhmi.edu ∙ Xinzhong Dong^1,2,7,8,10 

¹The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ²Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ³Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA ⁴Department of Neurosurgery, The Ohio State University College of Medicine, Columbus, OH 43210, USA ⁵Department of Neurology, The University of Texas Health Science Center Houston, McGovern Medical School, Houston, TX 77030, USA ⁶Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ⁷Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ⁸Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA ⁹ These authors contributed equally ¹⁰Lead contact

Publication History: Received December 20, 2024; Revised May 2, 2025; Accepted June 30, 2025; Published online July 24, 2025

DOI: 10.1016/j.cell.2025.06.045 External LinkAlso available on ScienceDirect External Link

Copyright: © 2025 The Author(s). Published by Elsevier Inc.

User License: Creative Commons Attribution (CC BY 4.0)

Highlights

• Mrgprb2/MRGPRX2 is a key receptor that activates meningeal mast cells after stroke
• Mrgprb2 regulates skull bone marrow neutrophil recruitment into the brain post-stroke
• Mast cell proteases cleave semaphorin, mediating neutrophil infiltration into the brain
• Inhibiting Mrgprb2 alleviates post-stroke brain inflammation and improves survival

Summary

The immune environment surrounding the brain plays a fundamental role in monitoring signs of injury. Insults, including ischemic stroke, can disrupt this balance and incite an exaggerated inflammatory response, yet the underlying mechanism remains unclear. Here, we show that the mast-cell-specific receptor Mrgprb2 regulates post-stroke brain inflammation from the meninges. Mrgprb2 causes meningeal mast cell degranulation after stroke, releasing immune mediators. This process recruits skull bone marrow neutrophils into the dura and further promotes neutrophil migration from the dura into the brain by cleaving the chemorepellent semaphorin 3a. We demonstrate that the human ortholog, MRGPRX2, is expressed in human meningeal mast cells and is activated by upregulation of the neuropeptide substance P following stroke. Pharmacologically inhibiting Mrgprb2 reduces post-stroke inflammation and improves neurological outcomes in mice, providing a druggable target. Collectively, our study identifies Mrgprb2 as a critical meningeal gatekeeper for immune migration from skull bone marrow reservoirs into the brain.

Estrogen alleviates acute and chronic itch in mice

DOI: 10.3892/etm.2023.11954

Abstract. Itching is associated with various skin diseases,including atopic dermatitis and allergic dermatitis, and leadsto repeated scratching behavior and unpleasant sensation.Although clinical and laboratory research data have shown that estrogen is involved in regulating itch, the molecular and cellular basis of estrogen in itch sensation remains elusive.In the present study, it was found that estrogen‑treated mice exhibited reduced scratching bouts when challenged with histamine, chloroquine, the proteinase‑activated receptor‑2 activating peptide SLIGRL‑NH2 (SLIGRL), compound48/80, and 5‑hydroxytryptamine when compared with mice in the placebo group. Moreover, estrogen also suppressed scratching bouts in the mouse model of chronic itch induced by acetone‑ether‑water treatment. Notably, consistent with the behavioral tests, the present RNA‑seq analysis showed that estrogen treatment caused significantly reduced expression levels of itch‑related molecules such as Mas‑related G‑protein coupled receptor member A3, neuromedin B and natriuretic polypeptide b. In addition, estradiol attenuated histamine‑induced and chloroquine‑induced calcium influx in dorsal root ganglion neurons. Collectively, the data of the present study suggested that estrogen modulates the expression of itch‑related molecules and suppresses both acute and chronic itch in mice.

Key words: itch, acute itch, chronic itch, estrogen, RNA‑sequencing, calcium imaging

^{Decreased Responsiveness to Chemical Itch in Old Mice}

Qiaofeng Zhao, Mitsutoshi Tominaga, Yayoi Kamata, Sumika Toyama, Kotaro Honda, Hang Ma, Eriko Komiya, and Kenji Takamori.

Abstract: Aging is associated with altered itch perception, potentially due to changes in neuronal function and pruriceptive signaling. The underlying mechanisms, however, remain unclear. We investigated age-related differences in itch sensitivity at behavioral, cellular, and molecular levels. Young and old mice were intradermally injected with various pruritogens, including small molecules (histamine, chloroquine, and serotonin). Additionally, immunofluorescence staining was performed to analyze the expression of TRPV1 and Cav3.2. Old mice exhibited reduced scratching behavior following injections, and their neuronal responses to histamine and chloroquine were diminished. Although all treated groups showed increased mechanical alloknesis, the effect was less pronounced in old animals. The expression of TRPV1 and Cav3.2 was also reduced in dorsal root ganglia neurons of old mice. These findings suggest that aging impairs both functional responsiveness and molecular signaling in sensory neurons, contributing to reduced chemical itch sensitivity in aged individuals.

Keywords: aging; calcium imaging; Cav3.2; dorsal root ganglion; pruritus; TRPV1; itch mechanisms

Rostral ventromedial medulla astrocytes regulate chronic itch and anxiety-related behaviors

Ting Yi ^ab1, Mengping Lou ^a1, Xinyi Gao ^a, Liyuan Bao ^a, Heting Yan ^a, Teng Lin ^a, Yayue Yang ^a, Tianchi Gao ^a, Chenghao Wang ^a, Jianyu Zhu ^a, Yanqing Wang ^ab, Wenli Mi ^a

^aDepartment of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China

^bChinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, 510006, China

Received 3 July 2024, Revised 1 February 2025, Accepted 5 February 2025, Available online 6 February 2025, Version of Record 11 February 2025.

Abstract

Itch (pruritus), a maladaptive and debilitating cutaneous symptom, is commonly associated with many skin conditions; however, the available therapies with sufficient efficacy are lacking. The role of astrocytes in the rostral ventromedial medulla (RVM), a crucial brain region in the descending pain modulation system, in chronic itch remains uncertain. In this study, we examined the chronic itch behavior and itch-related anxiety behavior in the diphenylcyclopripenone (DCP)-induced contact dermatitis mice, and also observed the activation of astrocytes in the RVM in the DCP mice. Reducing calcium signaling in astrocytes through global IP3R2 gene knockout, conditional astroglial IP3R2 gene knockout in the RVM, or microinjection of AAV-GfaABC1D-hPMCA2 w/b into the RVM, exhibited an anti-pruritic effect on the chronic itch. These findings suggest that RVM astrocytes play a role in regulating chronic itch, and interventions targeting astrocytic activation may offer potential relief for chronic itch.

Keywords

Chronic itch ; Astrocyte ; Rostral ventromedial medulla

Received 3 July 2024, Revised 1 February 2025, Accepted 5 February 2025, Available online 6 February 2025, Version of Record 11 February 2025.

Investigation of the participation of the TRPV1 receptor in the irritant effect of dithranol in mice

Abstract

Dithranol is one of the most effective topical medications for treating plaque psoriasis. However, its clinical use is
limited by irritative adverse reactions to the skin, such as oedema, erythema, and pruritus, caused by poorly
understood mechanisms. Because TRPV1 activation mediates skin irritation caused by several drugs, we conducted
blind and randomised experiments in male and female C57BL/6 mice to elucidate the role of TRPV1 in
dithranol-induced irritation. Dithranol (0.01%–0.5%) or vehicle was applied topically to the right ear of the
animals. Oedema, erythema, and pruritus were monitored from 2 h to 6 days after application. Treatment with
0.5% dithranol caused oedema and erythema, but not pruritus, starting at 6 h, reaching its highest point at 1 day,
and persisting up to 6 days after treatment, mainly in male mice. The 0.1% dose induced erythema but not
oedema. Interestingly, topical application of 1% capsaicin was shown to defunctionalise TRPV1-positive fibres
and did not influence early irritation caused by dithranol (2 h–2 days). However, it increased the late phase of
irritation (5–6 days). Similarly, salicylate did not reduce the early irritation caused by dithranol but also
increased the late phase. Antagonism by SB366791 and 4-tert-butylcyclohexanol did not alter skin irritation. Our
results suggest that, contrary to our initial hypothesis, TRPV1 appears to act protectively against skin irritation
caused by dithranol, particularly in the late stage.

keywords

Neurogenic inflammation
Anthralin
TRP channels
Psoriasis

authors

Ana Merian da Silva, Marcella de Amorim Ferreira,Roberta Giusti Schran,
Debora Denardin Lückemeyer, Arthur Silveira Prudente, Juliano Ferreira

Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain

DongYee Kim

Involvement of α-Melanocyte–Stimulating Hormone–Thromboxane A₂ System on Itching in Atopic Dermatitis

Tsugunobu Andoh ^∗, Chihiro Akasaka ^∗, Kyoko Shimizu ^†, Jung-Bum Lee ^‡, Yoko Yoshihisa ^†, Tadamichi Shimizu ^†

^∗Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

^†Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

^‡Laboratory of Medicinal Bio-resources, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

https://doi.org/10.1016/j.ajpath.2019.05.017

α-Melanocyte–stimulating hormone (α-MSH) is an endogenous peptide hormone involved in cutaneous pigmentation in atopic dermatitis (AD) with severe itching. α-MSH elicits itch-related responses in mice. We, therefore, investigated whether α-MSH was involved in itching in AD. In the skin of AD patients and mice with atopy-like dermatitis, α-MSH and the prohormone convertase 2, which is the key processing enzyme for the production of α-MSH, were distributed mainly in keratinocytes. In the skin of mice with dermatitis, melanocortin receptors (MC1R and MC5R) were expressed at the mRNA level and were distributed in the dermis. In the dorsal root ganglion of mice with dermatitis, mRNAs encoding MC1R, MC3R, and MC5R were also expressed. MC1R antagonist agouti-signaling protein inhibited spontaneous scratching in mice with dermatitis. In healthy mice, intradermal α-MSH elicited itch-associated responses, which were inhibited by thromboxane (TX) A₂ receptor antagonist ONO-3708. In mouse keratinocytes, α-MSH increased the production of TXA₂, which was inhibited by adenylyl cyclase inhibitor SQ-22536 and Ca²⁺chelatorEGTA. In mouse keratinocytes treated with siRNA for MC1R and/or MC5R, α-MSH–induced TXA₂ production was decreased. α-MSH increased intracellular Ca²⁺ ion concentration in dorsal root ganglion neurons and keratinocytes. These results suggest that α-MSH is involved in itching during AD and may elicit itching through the direct action of primary afferents and TXA₂ production by keratinocytes.

A microbial amino-acid-conjugated bile acid,tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE

Jun Lin ¹²³¹⁸, Qixing Nie ¹²⁴¹⁸, Jie Cheng ⁵⁶¹⁸, YaNi Zhong ⁵¹⁸, Tianyao Zhang ⁵¹⁸, Xiuying Zhang ⁷¹⁸, Xiaoyan Ge ⁶¹⁸, Yong Ding ¹²³¹⁸, Canyang Niu ⁵⁸, Yuhua Gao ¹²³, Kai Wang ¹²³, Mingxin Gao ⁹, Xuemei Wang ¹²³, Weixuan Chen ¹⁰, Chuyu Yun ¹⁰, Chuan Ye ¹²³, Jinkun Xu ¹²³, Weike Shaoyong ¹²³, Lijun Zhang ⁹, Pan Shang ⁵⁶, Xi Luo ¹²³, Zhiwei Zhang ¹²³, Xin Zheng ⁹, Xueying Sha ⁹, Jinxin Zhang ¹²³, Shaoping Nie ⁴, Xuguang Zhang ¹¹, Fazheng Ren ¹², Huiying Liu ¹²³, Erdan Dong ⁸¹³¹⁴, Xiao Yu ⁹, Linong Ji ⁷, Yanli Pang ¹¹⁵¹⁶, Jin-Peng Sun ⁵⁶, Changtao Jiang ^1231719

¹Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China²NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China³Department of Physiology and Pathophysiology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China⁴State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology, Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang, China⁵Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China⁶Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, China⁷Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Centre, Beijing, China⁸Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China⁹Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China¹⁰Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China¹¹Shanghai Institute of Nutrition and Health, The Chinese Academy of Sciences, Shanghai, China¹²Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, No. 10 Tianxiu Road, Haidian District, Beijing 100193, China¹³The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing, China¹⁴Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China¹⁵National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China¹⁶Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing, China¹⁷Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China

Received 25 February 2024, Revised 2 October 2024, Accepted 8 May 2025, Available online 29 May 2025.

https://doi.org/10.1016/j.cell.2025.05.010

Highlights

• Revealed microbiota-host interaction via microbial amino-acid-conjugated bile acids
• Trp-CA serves as the endogenous ligand of the orphan GPCR MRGPRE
• Identified a non-itch function of the itch family receptor MRGPRE in glucose control
• MRGPRE activation boosts GLP-1 secretion via the Gs-cAMP and β-arrestin-1-ALDOA pathways

Summary

Recently, microbial amino-acid-conjugated bile acids (MABAs) have been found to be prevalent in human samples. However, their physiological significance is still unclear. Here, we identify tryptophan-conjugated cholic acid (Trp-CA) as the most significantly decreased MABA in patients with type 2 diabetes (T2D), and its abundance is negatively correlated with clinical glycemic markers. We further demonstrate that Trp-CA improves glucose tolerance in diabetic mice. Mechanistically, we find that Trp-CA is a ligand of the orphan G protein-coupled receptor (GPCR) Mas-related G protein-coupled receptor family member E (MRGPRE) and determine the binding mode between the two. Both MRGPRE-Gs-cyclic AMP (cAMP) and MRGPRE-β-arrestin-1-aldolase A (ALDOA) signaling pathways contribute to the metabolic benefits of Trp-CA. Additionally, we find that the bacterial bile salt hydrolase/transferase of Bifidobacterium is responsible for the production of Trp-CA. Together, our findings pave the way for further research on MABAs and offer additional therapeutic targets for the treatment of T2D.

Luteolin Alleviates Oxidative Stress in Chronic Obstructive Pulmonary Disease Induced by Cigarette Smoke via Modulation of the TRPV1 and CYP2A13/NRF2 Signaling Pathways

https://doi.org/10.1016/j.phymed.2025.156564

Lina Zhou^1,2+, Tunyu Jian^1,+,Yan Wan² , Rizhong Huang² , Hailing Fang² , Yiwei Wang² , Chengyuan Liang¹,  Xiaoqin Ding^1,* and Jian Chen^1,2,*

1 Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of Botany,

Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China; linazhou1124@163.com (L.Z.);

jiantunyu1986@163.com (T.J.); liangcy618@cnbg.net (C.L.)

2 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China;

wany998061@163.com (Y.W.); 20210615@njucm.edu.cn (R.H.); fanghailing2013@163.com (H.F.);

yiweiwang@njucm.edu.cn (Y.W.)

* Correspondence: dingxiaoqin@jib.ac.cn (X.D.); chenjian@jib.ac.cn (J.C.); Tel.: +86-25-8434-7104 (X.D. & J.C.);

Fax: +86-25-8434-7081 (X.D. & J.C.)

† These authors contributed equally to this work.

Keywords

Cigarette smoke; chronic obstructive pulmonary disease (COPD); alveolar epithelial (A549) cells; luteolin; TPRV1; CYP2A13

Meningeal regulatory T cells inhibit nociception
In female mice

Élora Midavaine1, Beatriz C. Moraes1, Jorge Benitez1, Sian R. Rodriguez1, Joao M. Braz1, Nathan P. Kochhar1, Walter L. Eckalbar1, Lin Tian2, Ana I. Domingos3, John E. Pintar4,
Allan I. Basbaum1*†, Sakeen W. Kashem5,6

Pain prevalence is higher in women across multiple conditions, and chronic pain severity
is frequently altered during gender affirming hormonal therapy (1). Although
there is evidence that T cells contribute to sexually dimorphic pain processing, the exact
mechanisms remain unclear (2). Regulatory T cells (Treg cells) are a subset of CD4+ T cells
defined by the expression of the master transcriptional regulator FOXP3, which is encoded
by a gene found on the X chromosome. In addition to their critical function in restraining
inflammation, Treg cells are major contributors of tissue reparative and supportive functions
(3, 4). However, it is not known whether and how Treg cells directly alter neuronal activity to
modulate nociception, independently of their immunomodulatory functions (5, 6). In this
study, we examined the role of Treg cells in regulating pain sensing in mice.