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.
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.
Investigation of the participation of the TRPV1 receptor in the irritant effectof dithranol in mice
Ana Merian da Silva, Marcella de Amorim Ferreira, Roberta Giusti Schran, Debora Denardin Lückemeyer, Arthur Silveira Prudente, Juliano Ferreira
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.
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.
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
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.
A topical Chinese herbal inhibits pruritus and skin inflammation via neural TRPM8 in atopic dermatitis
Author links open overlay panelYao Chen a†, Ziyuan Tang a†, Zhiyao Han a, Mingyang Wang a, Xinran Li a, Luying Lai a, Pingzheng Zhou a,b, Fang Wang c,d, Fengxian Li a,e,**,‡
aDepartment of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, China bGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China cDepartment of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China dGuangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China eKey Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, China
Received 7 September 2024, Revised 12 February 2025, Accepted 15 February 2025, Available online 16 February 2025, Version of Record 21 February 2025.
Atopic dermatitis (AD) is a chronic, itchy, and inflammatory skin disease. The neuroimmune concept of itch involves aberrant immune responses and neural activities. Chinese herbal medicine has been demonstrated to alleviate AD symptoms, but the underlying mechanisms remain not fully understand.
Purpose
Chushizhiyang (CS) ointment is a topical treatment consisting of Chinese herbal ingredients. We aimed to study the underlying mechanism of CS on treating AD.
Method
To investigate the therapeutic efficacy of CS, we utilized a well-established atopic dermatitis mouse model, administering CS ointment topically to the ears. To unravel the underlying mechanisms, we employed a multifaceted approach, including behavioral assay, network pharmacology analysis, RNA-sequencing analysis, neural tracing, and calcium imaging. Additionally, transient receptor potential (TRP) M8-deficient mice were employed to validate the specific targets of CS.
Results
By employing a murine model of AD-like disease, we found that CS ointment can reduce skin inflammation and inhibit scratching behavior. Importantly, its capacity to alleviate itch-induced scratching surpasses that of topical steroid, a positive control treatment. The RNA-sequencing analysis of the affected skin revealed that the differentially expressed genes were enriched in neuroactive pathways that include ion channels particularly TRPM8. Calcium imaging demonstrated that CS ointment is capable of activating TRPM8-positive sensory neurons. Using transgenic animals, we found that CS ointment exhibited its anti-inflammatory or anti-pruritic effects only when TRPM8 is functional intact. Additionally, CS treatment reduced neuronal activities in wild-type, rather than TRPM8-compromised animals.
Conclusion
Our findings suggest that topical Chinese herbals participate in neuroimmune mechanisms for AD-like disease via TRPM8.
Keywords
Atopic dermatitis, TRPM8, Pruritus, Inflammation, Chinese herb
Abstract Mast cells (MCs) play a central role in allergic immune responses. MC activation is regulated by several inhibitory immunoreceptors. The CD300 family members CD300a and CD300lf recognize phospholipid ligands and inhibit the FcεRI-mediated activating signal in MCs. While CD300a binds to phosphatidylserine (PS) to inhibit MCs activation, CD300lf function is less clear due to its ability to bind with ceramide and PS. Moreover, it also remains blurring whether CD300a and CD300lf function independently, cooperatively, or by interfering with each other in regulating MC activation. Using imaging and flow cytometric analyses of bone marrow-derived cultured MCs (BMMCs) from wild-type (WT), Cd300a–/–, Cd300lf–/–, and Cd300a–/–Cd300lf–/– mice, we show that CD300lf and CD300a colocalized with PS externalized to the outer leaflet of the plasma membrane with a polar formation upon activation, and CD300lf cooperates with CD300a to inhibit BMMCs activation. CD300lf also colocalized with extracellular ceramide in addition to the internal PS on the cell surface, which results in stronger inhibition of MC activation than CD300lf binding to PS alone. Similarly, although both Cd300a–/– and Cd300lf–/– mice showed decreased rectal temperatures compared with WT mice in the model of passive systemic anaphylaxis, Cd300a–/–Cd300lf–/– mice showed lower rectal temperature than either Cd300a–/– or Cd300lf–/– mice. Our results demonstrate the cooperativity of multiple inhibitory receptors expressed on MCs and their regulatory functions upon binding to respective ligands. Keywords: CD300a, CD300lf, ceramide, mast cells, phosphatidylserine
