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FcαRI co-stimulation converts human intestinal CD103+ dendritic cells into pro-inflammatory cells through glycolytic reprogramming.

Nat Commun. 2018 Feb 28;9(1):863
Ivo S Hansen 1 , Lisette Krabbendam 1 , Jochem H Bernink 1 , Fabricio Loayza-Puch 2 , Willianne Hoepel 1 , Johan A van Burgsteden 1 , Elsa C Kuijper 3 , Christianne J Buskens 4 , Willem A Bemelman 4 , Sebastiaan A J Zaat 5 , Reuven Agami 2 , Gestur Vidarsson 6 , Gijs R van den Brink 7 , Esther C de Jong 1 , Manon E Wildenberg 7 , Dominique L P Baeten 1 , Bart Everts 3 , Jeroen den Dunnen 8
Ivo S Hansen 1 , Lisette Krabbendam 1 , Jochem H Bernink 1 , Fabricio Loayza-Puch 2 , Willianne Hoepel 1 , Johan A van Burgsteden 1 , Elsa C Kuijper 3 , Christianne J Buskens 4 , Willem A Bemelman 4 , Sebastiaan A J Zaat 5 , Reuven Agami 2 , Gestur Vidarsson 6 , Gijs R van den Brink 7 , Esther C de Jong 1 , Manon E Wildenberg 7 , Dominique L P Baeten 1 , Bart Everts 3 , Jeroen den Dunnen 8
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Author information
  • 1 Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
  • 2 Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 3 Department of Parasitology, Leiden University Medical Centre, University of Leiden, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • 4 Department of Surgery, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
  • 5 Department of Medical Microbiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
  • 6 Department of Experimental Immunohematology, Sanquin Research, University of Amsterdam, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands.
  • 7 Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
  • 8 Department of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.dendunnen@amc.nl.

摘要

CD103+ dendritic cells (DC) are crucial for regulation of intestinal tolerance in humans. However, upon infection of the lamina propria this tolerogenic response is converted to an inflammatory response. Here we show that immunoglobulin A (IgA) immune complexes (IgA-IC), which are present after bacterial infection of the lamina propria, are important for the induction of inflammation by the human CD103+SIRPα+ DC subset. IgA-IC, by recognition through FcαRI, selectively amplify the production of proinflammatory cytokines TNF, IL-1β and IL-23 by human CD103+ DCs. These cells then enhance inflammation by promoting Th17 responses and activating human intestinal innate lymphoid cells 3. Moreover, FcαRI-induced cytokine production is orchestrated via upregulation of cytokine translation and caspase-1 activation, which is dependent on glycolytic reprogramming mediated by kinases Syk, PI3K and TBK1-IKKε. Our data suggest that the formation of IgA-IC in the human intestine provides an environmental cue for the conversion of a tolerogenic to an inflammatory response.

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