Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models

Ghazl Al Hamwi¹, Mohamad Wessam Alnouri¹, Sven Verdonck ², Piotr Leonczak ², Shaswati Chaki ³, Stefan Frischbutter ^4,5,
Pavel Kolkhir^4,5, Michaela Matthey⁶, Constantin Kopp¹, Marek Bednarski⁷, Yvonne K. Riedel¹, Daniel Marx¹, Sophie Clemens¹,
Vigneshwaran Namasivayam ¹, Susanne Gattner¹, Dominik Thimm¹, Katharina Sylvester¹, Katharina Wolf^8,9, Andreas E. Kremer ^8,10,
Steven De Jonghe ², Daniela Wenzel^6,11, Magdalena Kotańska⁷, Hydar Ali ³, Piet Herdewijn² and Christa E. Müller ^1✉

¹PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany; ²Medicinal Chemistry,
Rega Institute for Medical Research, KU Leuven, Herestraat 49-box 1041, 3000 Leuven, Belgium; ³Department of Basic & Translational Sciences, School of Dental Medicine,
University of Pennsylvania, Philadelphia, PA 19104, USA; ⁴Institute of Allergology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and
Humboldt-Universität zu Berlin, 12203 Berlin, Germany; ⁵Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, 12203 Berlin,
Germany; ⁶Department of Systems Physiology, Institute of Physiology, Medical Faculty, Ruhr University of Bochum, 44801 Bochum, Germany; ⁷Department of Pharmacological
Screening, Jagiellonian University, Medical College, Medyczna 9, 30-688 Krakow, Poland; ⁸Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-
University Erlangen-Nürnberg, Nürnberg, Germany; ⁹Helmholtz Institute for Translational Oncology, Mainz (HI-TRON Mainz)—A Helmholtz Institute of the DKFZ, Mainz, Germany;
¹⁰Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland and ¹¹Institute of Physiology I, Life & Brain Center, Medical
Faculty, University of Bonn, 53127 Bonn, Germany
Correspondence: Christa E Müller (christa.mueller@uni-bonn.de)
These authors contributed equally: Ghazl Al Hamwi, Mohamad Wessam Alnouri, Sven Verdonck

Received: 14 August 2024 Revised: 24 February 2025 Accepted: 18 March 2025

Published online: 21 April 2025

Abstract

The MAS-related G protein-coupled receptor-X2 (MRGPRX2), an orphan receptor expressed on mast cells (MCs), is upregulated upon inflammation and induces hypersensitivity and inflammatory diseases. In contrast to the large number of MRGPRX2 agonists, only a few antagonists have been described, and no optimization has been reported to improve potency, selectivity, and drug-like properties. Antagonists with ancillary inhibition of the putative mouse ortholog MRGPRB2 have not been described. Here, we present a multi-disciplinary approach involving chemistry, biology, and computational science, resulting in the development of a small-molecule MRGPRX2 antagonist (PSB-172656, 3-ethyl-7,8-difluoro-2-isopropylbenzo[4,5]imidazo [1,2-a] pyrimidin-4(1H)-one) based on a fragment screening hit. The compound exhibits metabolic stability, low cytotoxicity, and competitive blockade of MRGPRX2 activation induced by a diverse range of agonists. It displays subnanomolar potency in Ca²⁺ mobilization assays (K_i value 0.142 nM) and was found to block MRGPRX2-mediated Gα_q and Gα_i1 dissociation, in addition to β-arrestin-2 recruitment. PSB-172656 is selective for MRGPRX2 versus all other MRGPRX subtypes. Its effect on MCs was confirmed in cell lines, including rat basophilic leukemia cells (RBL-2H3) recombinantly expressing human MRGPRX2, human Laboratory of Allergic Diseases 2 (LAD2) MCs, and native human skin MCs. PSB-172656 was found to additionally block the putative mouse ortholog of MRGPRX2, MRGPRB2, as determined in Ca²⁺ mobilization assays (K_i 0.302 nM), and to prevent mouse tracheal contractions, local allergic reactions, and systemic anaphylactic symptoms. PSB-172656 constitutes a unique pharmacological tool and has the potential to be developed as a drug for mast cell-mediated hypersensitivity reactions and chronic inflammatory diseases, addressing a huge unmet medical need.

Signal Transduction and Targeted Therapy volume 10, Article number: 128 (2025)

https://doi.org/10.1038/s41392-025-02209-8

In silico discovery of nanobody binders to a G protein coupled receptor using AlphaFold Multimer

Edward P. Harvey^1,* , Jeffrey S. Smith^{1,2, *}, Joseph D. Hurley^1,*, Alyana Granados³, Ernst W. Schmid¹, Jason G. Liang-Lin¹, Huyang Zhang¹, Emily M. Meara^1,2, Elizabeth K. Wren¹, Steffanie Paul^4,5, Matthew P. Ferguson¹, Victor G. Calvillo-Miranda¹, Miguel A. Alcantar^1,6, Debora S. Marks^4,5, Johannes C. Walter^1,7, Andrew C. Kruse^1,†, Katherine J. Susa^3,†

¹Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
²Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, 02115,USA.
³Department of Pharmaceutical Chemistry, University of California, San Francisco, CA94158, USA
⁴Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
⁵Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
⁶Department of Biomedical Engineering, University of California, Irvine, CA, 92697, USA
⁷Howard Hughes Medical Institute, Boston, MA, USA
^*These authors contributed equally.
^†Correspondence to: Andrew C. Kruse (Andrew_kruse@hms.harvard.edu) and Katherine J. Susa (Katherine.Susa@ucsf.edu)

• Received02 October 2025
• Accepted03 April 2026
• Published23 April 2026

https://doi.org/10.1038/s41467-026-72093-5

Azelaic acid potentiates TRPV3 activity as a mechanism for skin irritation

Diwas Rawal ^{1 2}, Wook-Joo Lee ^{1 2}, Won-Sik Shim ^{1 2*}

¹College of Pharmacy, Gachon University, Incheon, Republic of Korea ²Gachon Institute of Pharmaceutical Sciences, Incheon, Republic of Korea

*Corresponding author e-mail: wsshim@gachon.ac.kr

https://doi.org/10.1016/j.jid.2026.01.022

Processing of pain and itch information by modality-specific neurons within the anterior cingulate cortex in mice

Hyoung-Gon Ko^1,2,  Hyunsu Jung^#3,4,  Seunghyo Han^#5,  Dong Il Choi^#4,  Chiwoo Lee^#4,  Ja Eun Choi⁴,  Jihae Oh⁴,  Chuljung Kwak³,  Dae Hee Han³,  Jun-Nyeong Kim⁵,  Sanghyun Ye⁴,  Jiah Lee⁴,  Jaehyun Lee⁴,  Kyungmin Lee⁶,  Jae-Hyung Lee⁷,  Min Zhuo^8,9 &  Bong-Kiun Kaang^10,11

¹Department of Anatomy and Neurobiology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, 2177 Dalgubeol-daero, Daegu, South Korea. hgko@khu.ac.kr.²Department of Oral Anatomy and Developmental Biology, Kyung Hee University College of Dentistry, Seoul, South Korea. hgko@khu.ac.kr.³Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea.⁴Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea.⁵Department of Anatomy and Neurobiology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, 2177 Dalgubeol-daero, Daegu, South Korea.⁶Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science and Engineering Institute, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Daegu, South Korea.⁷Department of Oral Microbiology, College of Dentistry, Kyung Hee University, 26 Kyungheedae-ro, Seoul, South Korea.⁸Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada.⁹International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China.¹⁰Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea. kaang@ibs.re.kr.¹¹Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea. kaang@ibs.re.kr.^#Contributed equally.

• PMID: 40038260
• PMCID: PMC11880300
• DOI: 10.1038/s41467-025-57041-z

Abstract

Pain and itch are aversive sensations with distinct qualities, processed in overlapping pathways and brain regions, including the anterior cingulate cortex (ACC), which is critical for their affective dimensions. However, the cellular mechanisms underlying their processing in the ACC remain unclear. Here, we identify modality-specific neuronal populations in layer II/III of the ACC in mice involved in pain and itch processing. Using a synapse labeling tool, we show that pain- and itch-related neurons selectively receive synaptic inputs from mediodorsal thalamic neurons activated by pain and itch stimuli, respectively. Chemogenetic inhibition of these neurons reduced pruriception or nociception without affecting the opposite modality. Conversely, activation of these neurons did not enhance stimulus-specific responses but commonly increased freezing-like behavior. These findings reveal that the processing of itch and pain information in the ACC involves activity-dependent and modality-specific neuronal populations, and that pain and itch are processed by functionally distinct ACC neuronal subsets.

Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors

Xueke Li MSc ^a∗, Haifeng Yang MSc ^a∗, Yuewen Han MSc ^a, Shijin Yin PhD ^b, Bingzheng Shen PhD ^a, Yingliang Wu PhD ^a, Wenxin Li PhD ^a, Zhijian Cao PhD ^a c d

^aState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China ^bSchool of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China ^cBio-drug Research Center, Wuhan University, Wuhan, China ^dHubei Province Engineering and Technology Research, Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan, China

Received 4 May 2020, Revised 21 November 2020, Accepted 2 December 2020, Available online 22 December 2020, Version of Record 3 June 2021.

https://doi.org/10.1016/j.jaci.2020.12.626

Background

Tick bites severely threaten human health because they allow the transmission of many deadly pathogens, including viruses, bacteria, protozoa, and helminths. Pruritus is a leading symptom of tick bites, but its molecular and neural bases remain elusive.

Objectives

This study sought to discover potent drugs and targets for the specific prevention and treatment of tick bite–induced pruritus and arthropod-related itch.

Methods

We used live-cell calcium imaging, patch-clamp recordings, and genetic ablation and evaluated mouse behavior to investigate the molecular and neural bases of tick bite–induced pruritus.

Results

We found that 2 tick salivary peptides, IP defensin 1 (IPDef1) and IR defensin 2 (IRDef2), induced itch in mice. IPDef1 was further revealed to have a stronger pruritogenic potential than IRDef2 and to induce pruritus in a histamine-independent manner. IPDef1 evoked itch by activating mouse MrgprC11 and human MRGPRX1 on dorsal root ganglion neurons. IPDef1-activated MrgprC11/X1 signaling sensitized downstream ion channel TRPV1 on dorsal root ganglion neurons. Moreover, IPDef1 also activated mouse MrgprB2 and its ortholog human MRGPRX2 selectively expressed on mast cells, inducing the release of inflammatory cytokines and driving acute inflammation in mice, although mast cell activation did not contribute to oxidated IPDef1–induced itch.

Conclusions

Our study identifies tick salivary peptides as a new class of pruritogens that initiate itch through MrgprC11/X1-TRPV1 signaling in pruritoceptors. Our work will provide potential drug targets for the prevention and treatment of pruritus induced by the bites or stings of tick and maybe other arthropods.

“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.

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.

TPepPro: a deep learning model for predicting peptide–protein interactions

Xiaohong Jin, Zimeng Chen, Dan Yu, Qianhui Jiang, Zhuobin Chen, Bin Yan, Jing Qin, Yong Liu, Junwen Wang 

Bioinformatics, Volume 41, Issue 1, January 2025, btae708, https://doi.org/10.1093/bioinformatics/btae708

Published:

25 November 2024

 Article history

Abstract

Motivation

Peptides and their derivatives hold potential as therapeutic agents. The rising interest in developing peptide drugs is evidenced by increasing approval rates by the FDA of USA. To identify the most potential peptides, study on peptide-protein interactions (PepPIs) presents a very important approach but poses considerable technical challenges. In experimental aspects, the transient nature of PepPIs and the high flexibility of peptides contribute to elevated costs and inefficiency. Traditional docking and molecular dynamics simulation methods require substantial computational resources, and the predictive accuracy of their results remain unsatisfactory.

Results

To address this gap, we proposed TPepPro, a Transformer-based model for PepPI prediction. We trained TPepPro on a dataset of 19,187 pairs of peptide-protein complexes with both sequential and structural features. TPepPro utilizes a strategy that combines local protein sequence feature extraction with global protein structure feature extraction. Moreover, TPepPro optimizes the architecture of structural featuring neural network in BN-ReLU arrangement, which notably reduced the amount of computing resources required for PepPIs prediction. According to comparison analysis, the accuracy reached 0.855 in TPepPro, achieving an 8.1% improvement compared to the second-best model TAGPPI. TPepPro achieved an AUC of 0.922, surpassing the second-best model TAGPPI with 0.844. Moreover, the newly developed TPepPro identify certain PepPIs that can be validated according to previous experimental evidence, thus indicating the efficiency of TPepPro to detect high potential PepPIs that would be helpful for amino acid drug applications.

Availability and implementation

The source code of TPepPro is available at https://github.com/wanglabhku/TPepPro.

Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation

Andrew W. Liu^1,2, Youran R. Zhang^1,2, Chien-Sin Chen^1,2, Tara N. Edwards^1,2, Sumeyye Ozyaman^1,2†,
Torben Ramcke^1,2, Lindsay M. McKendrick^1,2, Eric S. Weiss^1,2, Jacob E. Gillis^1,2, Colin R. Laughlin²‡,
Simran K. Randhawa², Catherine M. Phelps², Kazuo Kurihara^1,2, Hannah M. Kang^1,2,
Sydney-Lam N. Nguyen^1,2, Jiwon Kim3, Tayler D. Sheahan3§, Sarah E. Ross3,4, Marlies Meisel^2,5,
Tina L. Sumpter^1,2, Daniel H. Kaplan^1,2*

¹Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA. ²Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. ³Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA. ⁴Pittsburgh Center for Pain Research, Pittsburgh, PA, USA. ⁵Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
*Corresponding author. Email: dankaplan@pitt.edu
†Present address: Department of Histology and Embryology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
‡Present address: Department of Immunobiology, Yale University, New Haven, CT, USA.
§Present address: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.

Editor’s summary

Itch, the sensation that stimulates scratching behavior, is often triggered by skin irritants and inflammation. Liu et al. found that ablating itch-sensing neurons or physically preventing scratching decreased the inflammation associated with antigen-dependent mast cell responses in response to chemicals that induce allergic immune responses (see the Perspective by Ver Heul). Scratching promoted pain-sensing neurons to release a neuropeptide that stimulated mast cells, and this peptide hormone synergized with antigen-dependent activation to increase the mast cell’s degranulation and ability to produce inflammatory mediators. In a model of skin infection associated with antigen-specific mast cell responses, scratching contributed to decreasing the bacterial load. —Sarah H. Ross

Divergent sensory pathways of sneezing and coughing

Haowu Jiang ¹⁴, Huan Cui ¹⁴, Mengyu Chen ¹, Fengxian Li ¹, Xiaolei Shen ¹, Changxiong J. Guo ¹, George E. Hoekel ¹, Yuyan Zhu ², Liang Han ², Kangyun Wu ³, Michael J. Holtzman ³, Qin Liu ¹⁵

¹Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA

²The School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA

³Pulmonary and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA

4These authors contributed equally

https://doi.org/10.1016/j.cell.2024.08.009

Highlights

• Sneezing and coughing are mediated by distinct sensory populations
• Nasal MrgprC11-expressing sensory neurons serve as a core “sneeze” population
• Airway SST-expressing sensory neurons mediate chemically induced cough
• Sneezing and coughing are transmitted and modulated by divergent neuropathways

Summary

Sneezing and coughing are primary symptoms of many respiratory viral infections and allergies. It is generally assumed that sneezing and coughing involve common sensory receptors and molecular neurotransmission mechanisms. Here, we show that the nasal mucosa is innervated by several discrete populations of sensory neurons, but only one population (MrgprC11⁺MrgprA3⁻) mediates sneezing responses to a multitude of nasal irritants, allergens, and viruses. Although this population also innervates the trachea, it does not mediate coughing, as revealed by our newly established cough model. Instead, a distinct sensory population (somatostatin [SST⁺]) mediates coughing but not sneezing, unraveling an unforeseen sensory difference between sneezing and coughing. At the circuit level, sneeze and cough signals are transmitted and modulated by divergent neuropathways. Together, our study reveals the difference in sensory receptors and neurotransmission/modulation mechanisms between sneezing and coughing, offering neuronal drug targets for symptom management in respiratory viral infections and allergies.