Magniez, A. | bioRxiv Science

bioRxiv2025

Inhibition of IL-22-producing cells by Sutterella sp. bacteria

The gut microbiota constitutes a complex ecosystem essential for host defense against infection and maturation of the immune system. Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohns disease, are characterized by a severe inflammation of the intestine, arising from dysregulated control of host-microbiota crosstalk. However, neither the genetic bases of IBD nor the immune responses involved are fully understood. The pathobionts are currently under investigation for their active role in the development and the severity of IBD. These bacteria are present in the microbiota of healthy individuals without causing disease but have pathogenic potential when the intestinal environment is disturbed. Here, we highlighted Sutterella sp. as a new commensal pathobiont for its capacity to modulate the host immune functions. This anaerobic Gram-negative bacterium inhibits IL-22 production and AhR activity in mice and humans. The effectors responsible for the biological activity are large (>30 kDa) protein-based compounds secreted by Sutterella sp. These data enhance our understanding of the mechanisms that regulate host immune functions and pave the way for new therapeutic strategies to control gut inflammation.

immunology↗

bioRxiv2022

CARD9 in Neutrophils Protects from Colitis and Controls Mitochondrial Metabolism and Cell Survival

ObjectivesInflammatory 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. DesignWe 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). ResultsLymphocytes 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 in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. ConclusionThese 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. Summary boxO_LIWhat is already known about this subject? O_LIInflammatory bowel disease (IBD) results from genetic predisposition, microbiota dysbiosis and environmental factors, but the alterations of the immune response leading to chronic intestinal inflammation are still not fully understood. C_LIO_LICaspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. C_LIO_LIHowever, the cell types and cellular mechanisms involved in the CARD9 protective role against inflammation remain unknown. C_LI C_LIO_LIWhat are the new findings? O_LICARD9 expression in neutrophils, but not in lymphocytes, epithelial cells or CD11c+ cells, protects against DSS-induced colitis. C_LIO_LIIn the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. C_LIO_LIThe decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. C_LI C_LIO_LIHow might it impact on clinical practice in the foreseeable future? O_LIThese results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation. C_LIO_LIUnderstanding the role of neutrophils in chronic inflammation could lead to innovative therapeutic strategies targeting these key immune cells for various complex diseases. C_LI C_LI

immunology↗

bioRxiv2020

Erythropoietin directly affects single hematopoietic stem cell differentiation after transplantation

The cytokine erythropoietin (EPO) is a potent inducer of erythrocyte development and one of the most prescribed biopharmaceuticals. The action of EPO on erythroid progenitor cells is well established, but its direct action on hematopoietic stem and progenitor cells (HSPCs) is still debated. Here, using cellular barcoding, we traced the differentiation of hundreds of single murine HSPCs, after ex vivo EPO-exposure and transplantation, in five different hematopoietic cell lineages, and observed the transient occurrence of high-output Myeloid-Erythroid-megaKaryocyte (MEK)-biased and Myeloid-B-cell-Dendritic cell (MBDC)-biased clones. Single-cell RNA sequencing (ScRNAseq) analysis of ex vivo EPO-exposed HSPCs revealed that EPO induced the upregulation of erythroid associated genes in a subset of HSPCs, overlapping with multipotent progenitor (MPP) 1 and MPP2. Transplantation of Barcoded EPO-exposed-MPP2 confirmed their enrichment in Myeloid-Erythroid-biased clones. Collectively, our data show that EPO does act directly on MPP independent of the niche, and modulates fate by remodeling the clonal composition of the MPP pool.

immunology↗