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Browsing by Author "Demengeot, J"

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  • Host and microbiota interactions are critical for development of murine Crohn’s-like ileitis
    Publication . Roulis, M; Bongers, G; Armaka, M; Salviano, T; He, Z; Singh, A; Seidler, U; Becker, C; Demengeot, J; Furtado, G C; Lira, S A; Kollias, G
    Deregulation of host-microbiota interactions in the gut is a pivotal characteristic of Crohn's disease. It remains unclear, however, whether commensals and/or the dysbiotic microbiota associated with pathology in humans are causally involved in Crohn's pathogenesis. Here, we show that Crohn's-like ileitis in Tnf(ΔARE/+) mice is microbiota-dependent. Germ-free Tnf(ΔARE/+) mice are disease-free and the microbiota and its innate recognition through Myd88 are indispensable for tumor necrosis factor (TNF) overexpression and disease initiation in this model. The epithelium of diseased mice shows no major defects in mucus barrier and paracellular permeability. However, Tnf(ΔARE/+) ileitis associates with the reduction of lysozyme-expressing Paneth cells, mediated by adaptive immune effectors. Furthermore, we show that established but not early ileitis in Tnf(ΔARE/+) mice involves defective expression of antimicrobials and dysbiosis, characterized by Firmicutes expansion, including epithelial-attaching segmented filamentous bacteria, and decreased abundance of Bacteroidetes. Microbiota modulation by antibiotic treatment at an early disease stage rescues ileitis. Our results suggest that the indigenous microbiota is sufficient to drive TNF overexpression and Crohn's ileitis in the genetically susceptible Tnf(ΔARE/+) hosts, whereas dysbiosis in this model results from disease-associated alterations including loss of lysozyme-expressing Paneth cells.
    2016-05Journal article Restricted access Show more
  • Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide
    Publication . Caramalho, I.; Lopes-Carvalho, T.; Ostler, D.; Zelenay, S.; Haury, M; Demengeot, J
    Regulatory CD4 T cells (Treg) control inflammatory reactions to commensal bacteria and opportunist pathogens. Activation of Treg functions during these processes might be mediated by host-derived proinflammatory molecules or directly by bacterial products. We tested the hypothesis that engagement of germline-encoded receptors expressed by Treg participate in the triggering of their function. We report that the subset of CD4 cells known to exert regulatory functions in vivo (CD45RB(low) CD25(+)) selectively express Toll-like receptors (TLR)-4, -5, -7, and -8. Exposure of CD4(+) CD25(+) cells to the TLR-4 ligand lipopolysaccharide (LPS) induces up-regulation of several activation markers and enhances their survival/proliferation. This proliferative response does not require antigen-presenting cells and is augmented by T cell receptor triggering and interleukin 2 stimulation. Most importantly, LPS treatment increases CD4(+) CD25(+) cell suppressor efficiency by 10-fold and reveals suppressive activity in the CD4(+) CD45RB(low) CD25(-) subset that when tested ex-vivo, scores negative. Moreover, LPS-activated Treg efficiently control naive CD4 T cell-dependent wasting disease. These findings provide the first evidence that Treg respond directly to proinflammatory bacterial products, a mechanism that likely contributes to the control of inflammatory responses
    2003-02-17Journal article Open access Show more