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

Ivo S. Hansen, Lisette Krabbendam, Jochem H. Bernink, Fabricio Loayza-Puch, Willianne Hoepel, Johan A. van Burgsteden, Elsa C. Kuijper, Christianne J. Buskens, Willem A. Bemelman, Sebastiaan A. J. Zaat, Reuven Agami, Gestur Vidarsson, Gijs R. van den Brink, Esther C. de Jong, Manon E. Wildenberg, Dominique L. P. Baeten, Bart Everts and Jeroen den Dunnen ()
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Ivo S. Hansen: University of Amsterdam
Lisette Krabbendam: University of Amsterdam
Jochem H. Bernink: University of Amsterdam
Fabricio Loayza-Puch: Netherlands Cancer Institute
Willianne Hoepel: University of Amsterdam
Johan A. van Burgsteden: University of Amsterdam
Elsa C. Kuijper: Leiden University Medical Centre, University of Leiden
Christianne J. Buskens: University of Amsterdam
Willem A. Bemelman: University of Amsterdam
Sebastiaan A. J. Zaat: University of Amsterdam
Reuven Agami: Netherlands Cancer Institute
Gestur Vidarsson: University of Amsterdam
Gijs R. van den Brink: University of Amsterdam
Esther C. de Jong: University of Amsterdam
Manon E. Wildenberg: University of Amsterdam
Dominique L. P. Baeten: University of Amsterdam
Bart Everts: Leiden University Medical Centre, University of Leiden
Jeroen den Dunnen: University of Amsterdam

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03318-5

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