Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay

Affiliations
  • 1Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster 48149, Germany. Electronic address: michael.mihlan@uni-muenster.de.
  • 2Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Institute for Biomechanics, ETH Zürich, Zürich 8092, Switzerland.
  • 3Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Roche Pharma Research and Early Development (pRED), Cardiovascular, Metabolism, Immunology, Infectious Diseases and Ophthalmology (CMI2O), Roche Innovation Center, Basel 4070, Switzerland.
  • 4Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
  • 5Department of Dermatology, Universitätsklinikum Münster, Münster 48149, Germany.
  • 6Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Berlin 12203, Germany; Charité-Universitätsmedizin Berlin, Institute of Allergology, Berlin 12203, Germany.
  • 7Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany.
  • 8Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
  • 9Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster 48149, Germany.
  • 10Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Institut Curie, PSL Research University, INSERM U932, Paris 75005, France.
  • 11Institute of Nutritional Medicine, University of Hohenheim, Stuttgart 70593, Germany.
  • 12Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven 3000, Belgium; Center for Biotechnology, Khalifa University of Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates.
  • 13Department of Biochemistry, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan.
  • 14Department of Cardiology and Angiology, University Heart Center and Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
  • 15Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Medical Research Council (MRC) Toxicology Unit and Department of Genetics, University of Cambridge, Cambridge CB21QR, UK.
  • 16Medical Biology and Electron Microscopy Center, Rostock University Medical Center, Rostock 18057, Germany; Department Life, Light and Matter, Rostock University, Rostock 18051, Germany.

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Abstract

Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them. MCs release the attractant leukotriene B4 to re-route neutrophils toward them, thus exploiting a chemotactic system that neutrophils normally use for intercellular communication. After MC intracellular trap (MIT) formation, neutrophils die, but their undigested material remains inside MC vacuoles over days. MCs benefit from MIT formation, increasing their functional and metabolic fitness. Additionally, they are more pro-inflammatory and can exocytose active neutrophilic compounds with a time delay (nexocytosis), eliciting a type 1 interferon response in surrounding macrophages. Together, our study highlights neutrophil trapping and nexocytosis as MC-mediated processes, which may relay neutrophilic features over the course of chronic allergic inflammation.

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