PT  - JOURNAL ARTICLE
AU  - Danne, Camille
AU  - Michaudel, Chloé
AU  - Skerniskyte, Jurate
AU  - Planchais, Julien
AU  - Magniez, Aurélie
AU  - Agus, Allison
AU  - Michel, Marie-Laure
AU  - Lamas, Bruno
AU  - Da Costa, Gregory
AU  - Spatz, Madeleine
AU  - Oeuvray, Cyriane
AU  - Galbert, Chloé
AU  - Poirier, Maxime
AU  - Wang, Yazhou
AU  - Lapière, Alexia
AU  - Rolhion, Nathalie
AU  - Ledent, Tatiana
AU  - Pionneau, Cédric
AU  - Chardonnet, Solenne
AU  - Bellvert, Floriant
AU  - Cahoreau, Edern
AU  - Rocher, Amandine
AU  - Arguello, Rafael Rose
AU  - Peyssonnaux, Carole
AU  - Louis, Sabine
AU  - Richard, Mathias L
AU  - Langella, Philippe
AU  - El-Benna, Jamel
AU  - Marteyn, Benoit
AU  - Sokol, Harry
TI  - CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival
AID  - 10.1136/gutjnl-2022-326917
DP  - 2023 Jun 01
TA  - Gut
PG  - 1081--1092
VI  - 72
IP  - 6
4099  - http://gut.bmj.com/content/72/6/1081.short
4100  - http://gut.bmj.com/content/72/6/1081.full
SO  - Gut2023 Jun 01; 72
AB  - 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.All data relevant to the study are included in the article or uploaded as online supplemental information.