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Orléans, France

Bruchard M.,French Institute of Health and Medical Research | Bruchard M.,University of Burgundy | Rebe C.,French Institute of Health and Medical Research | Rebe C.,University of Burgundy | And 31 more authors.
Nature Immunology | Year: 2015

The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4+ T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation. © 2015, Nature Publishing Group. All rights reserved. Source


Palomo J.,French National Center for Scientific Research | Palomo J.,University of Orle Ans | Marchiol T.,Artimmune | Piotet J.,French National Center for Scientific Research | And 15 more authors.
PLoS ONE | Year: 2014

Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1β in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background (Cftrtm1eur or d/d), on double deficient for d/d and type 1 interleukin-1 receptor (d/d X IL-1R1-/-), and antibody neutralization. At steady state, young adult d/d mice did not show any signs of spontaneous lung inflammation. However, IL-1R1 deficiency conferred partial protection to repeated P. aeruginosa endotoxins/LPS lung instillation in d/d mice, as 50% of d/d mice succumbed to inflammation, whereas all d/d x IL-1R1-/- double mutants survived with lower initial weight loss and less pulmonary collagen and mucus production, suggesting that the absence of IL-1R1 signaling is protective in d/d mice in LPS-induced lung damage. Using P. aeruginosa acute lung infection we found heightened neutrophil recruitment in d/d mice with higher epithelial damage, increased bacterial load in BALF, and augmented IL-1β and TNF-α in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1β signaling in response to P. aeruginosa. IL-1β antibody neutralization had no effect on lung homeostasis in either d/d or WT mice, however P. aeruginosa induced lung inflammation and bacterial load were diminished by IL-1β antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1β production and reduced bacterial clearance. Further, we show that neutralization of IL-1β in d/d mice through the double mutation d/d x IL-1R1-/- and in WT via antibody neutralization attenuates inflammation. This supports the notion that intervention in the IL-1R1/IL-1β pathway may be detrimental in CF patients. © 2014 Palomo et al. Source


Palomo J.,French National Center for Scientific Research | Palomo J.,University of Orleans | Fauconnier M.,French National Center for Scientific Research | Fauconnier M.,University of Orleans | And 19 more authors.
European Journal of Immunology | Year: 2013

Cerebral malaria is a severe complication of Plasmodium falciparum infection. Although T-cell activation and type II IFN-γ are required for Plasmodium berghei ANKA (PbA)-induced murine experimental cerebral malaria (ECM), the role of type I IFN-α/β in ECM development remains unclear. Here, we address the role of the IFN-α/β pathway in ECM devel-opment in response to hepatic or blood-stage PbA infection, using mice deficient for types I or II IFN receptors. While IFN-γR1-/- mice were fully resistant, IFNAR1-/- mice showed delayed and partial protection to ECM after PbA infection. ECM resistance in IFN-γR1-/- mice correlated with unaltered cerebral microcirculation and absence of ischemia, while WT and IFNAR1-/- mice developed distinct microvascular pathologies. ECM resistance appeared to be independent of parasitemia. Instead, key mediators of ECM were attenuated in the absence of IFNAR1, including PbA-induced brain sequestration of CXCR3+-activated CD8+ T cells. This was associated with reduced expression of Granzyme B, IFN-γ, IL-12Rβ2, and T-cell-attracting chemokines CXCL9 and CXCL10 in IFNAR1-/- mice, more so in the absence of IFN-γR1. Therefore, the type I IFN-α/β receptor pathway contributes to brain T-cell responses and microvascular pathology, although it is not as essential as IFN-γ for the development of cerebral malaria upon hepatic or blood-stage PbA infection. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

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