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Interleukin-33 Signaling Controls the Development of Iron-Recycling Macrophages.

Immunity. 2020 May 19;52(5):782-793.e5. Epub 2020 Apr 08
Yuning Lu 1 , Gemma Basatemur 1 , Ian C Scott 2 , Davide Chiarugi 3 , Marc Clement 1 , James Harrison 1 , Ravin Jugdaohsingh 4 , Xian Yu 1 , Stephen A Newland 1 , Helen E Jolin 5 , Xuan Li 1 , Xiao Chen 6 , Monika Szymanska 7 , Guttorm Haraldsen 7 , Gaby Palmer 8 , Padraic G Fallon 9 , E Suzanne Cohen 10 , Andrew N J McKenzie 5 , Ziad Mallat 11
Yuning Lu 1 , Gemma Basatemur 1 , Ian C Scott 2 , Davide Chiarugi 3 , Marc Clement 1 , James Harrison 1 , Ravin Jugdaohsingh 4 , Xian Yu 1 , Stephen A Newland 1 , Helen E Jolin 5 , Xuan Li 1 , Xiao Chen 6 , Monika Szymanska 7 , Guttorm Haraldsen 7 , Gaby Palmer 8 , Padraic G Fallon 9 , E Suzanne Cohen 10 , Andrew N J McKenzie 5 , Ziad Mallat 11
+ et al

[No authors listed]

Author information
  • 1 Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
  • 2 Translational Sciences and Experimental Medicine, Early Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 3 The Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge, UK.
  • 4 Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
  • 5 Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
  • 6 Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
  • 7 Department of Pathology, Oslo University Hospital Rikshospitalet, Norway.
  • 8 Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland; Department of Pathology-Immunology, University of Geneva School of Medicine, Geneva, Switzerland.
  • 9 School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • 10 Bioscience Asthma, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 11 Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK; Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France. Electronic address: zm255@medschl.cam.ac.uk.

摘要


Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes and co-cooperated with heme to promote the generation of mature RPMs through activation of the MyD88 adaptor protein and ERK1/2 kinases downstream of the IL-33 receptor, IL1RL1. IL-33- and IL1RL1-deficient mice showed defective iron recycling and increased splenic iron deposition. Gene expression and chromatin accessibility studies revealed a role for GATA transcription factors downstream of IL-33 signaling during the development of pre-RPMs that retained full potential to differentiate into RPMs. Thus, IL-33 instructs the development of RPMs as a response to physiological erythrocyte damage with important implications to iron recycling and iron homeostasis.

KEYWORDS: erythrophagocytosis, interleukin-33, interleukin-33 receptor, interleukins, iron metabolism, red pulp macrophage