Philipp Starkl, Gustav Jonsson, Tyler Artner, Bruna Lenfers Turnes, Laura-Marie Gail, Tiago Oliveira, Aakanksha Jain, Nadine Serhan, Karel Stejskal, Karin Lakovits, Anastasiya Hladik, Meilin An, Keith M. Channon, Hail Kim, Thomas Köcher, Wolfgang Weninger, Georg Stary, Sylvia Knapp, Victoria Klang, Nicolas Gaudenzio, Clifford J. Woolf, Shweta Tikoo, Rohit Jain, Josef M. Penninger, Shane J. F. Cronin
{"title":"Mast cell–derived BH4 and serotonin are critical mediators of postoperative pain","authors":"Philipp Starkl, Gustav Jonsson, Tyler Artner, Bruna Lenfers Turnes, Laura-Marie Gail, Tiago Oliveira, Aakanksha Jain, Nadine Serhan, Karel Stejskal, Karin Lakovits, Anastasiya Hladik, Meilin An, Keith M. Channon, Hail Kim, Thomas Köcher, Wolfgang Weninger, Georg Stary, Sylvia Knapp, Victoria Klang, Nicolas Gaudenzio, Clifford J. Woolf, Shweta Tikoo, Rohit Jain, Josef M. Penninger, Shane J. F. Cronin","doi":"10.1126/sciimmunol.adh0545","DOIUrl":null,"url":null,"abstract":"<div >Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of <i>Gch1</i>, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell–specific <i>Gch1</i> or <i>Tph1</i> showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P–driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 98","pages":""},"PeriodicalIF":17.6000,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/sciimmunol.adh0545","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell–specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P–driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.
期刊介绍:
Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.