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CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival

Camille Danne 1, 2 Chloé Michaudel 3, 4 Jurate Skerniskyte 5 Julien Planchais 3, 4 Aurélie Magniez 4, 1 Allison Agus 1, 4 Marie-Laure Michel 1, 4 Bruno Lamas 1, 4 Gregory da Costa 1, 4 Madeleine Spatz 1, 4 Cyriane Oeuvray 2, 4 Chloé Galbert 2, 4 Maxime Poirier 1, 4 Yazhou Wang 1, 4 Alexia Lapière 1, 4 Nathalie Rolhion 2, 4 Tatiana Ledent 2 Cédric Pionneau 6 Solenne Chardonnet 6 Floriant Bellvert 7, 8 Edern Cahoreau 7, 8 Amandine Rocher 7 Rafael Rose Arguello 9 Carole Peyssonnaux 10 Sabine Louis 11 Mathias Richard 1, 4 Philippe Langella 1, 4 Jamel El-Benna 12 Benoit Marteyn 5, 13, 14 Harry Sokol 1, 2, 4 
Abstract : Objectives Inflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 ( Card9 ), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown. Design We used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real-time bioenergetic profile analysis (Seahorse). Results Lymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction increases mitochondrial reactive oxygen species production leading to the premature death of neutrophilsthrough apoptosis, especially in oxidative environment. The decreased functional neutrophils in tissues might explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. Conclusion These results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils.
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Submitted on : Monday, October 3, 2022 - 3:10:54 PM
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Camille Danne, Chloé Michaudel, Jurate Skerniskyte, Julien Planchais, Aurélie Magniez, et al.. CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival. Gut, 2022, pp.gutjnl-2022-326917. ⟨10.1136/gutjnl-2022-326917⟩. ⟨hal-03791244v2⟩



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