Institute Federatif Of Recherche 142
Institute Federatif Of Recherche 142
Frellstedt L.,University of Liège |
Frellstedt L.,National Veterinary School of Alfort |
Frellstedt L.,Institute Federatif Of Recherche 142 |
Waldschmidt I.,National Veterinary School of Alfort |
And 21 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2014
In humans, strenuous exercise causes increased susceptibility to respiratory infections associated with down-regulated expression of Toll-like receptors (TLRs) and costimulatory and antigen-presenting molecules. Lower airway diseases are also a common problem in sport and racing horses. Because innate immunity plays an essential role in lung defense mechanisms, we assessed the effect of acute exercise and training on innate immune responses in two different compartments. Blood monocytes and pulmonary alveolar macrophages (PAMs) were collected from horses in untrained, moderately trained, intensively trained, and deconditioned states before and after a strenuous exercise test. The cells were analyzed for TLR messenger ribonucleic acid (mRNA) expression by real-time PCR in vitro, and cytokine production after in vitro stimulation with TLR ligands was measured by ELISA. Our results showed that training, but not acute exercise, modified the innate immune responses in both compartments. The mRNA expression of TLR3 was down-regulated by training in both cell types, whereas the expression of TLR4 was up-regulated in monocytes. Monocytes treated with LPS and a synthetic diacylated lipoprotein showed increased cytokine secretion in trained and deconditioned subjects, indicating the activation of cells at the systemic level. The production of TNF-α and IFN-β in nonstimulated and stimulated PAMs was decreased in trained and deconditioned horses and might therefore explain the increased susceptibility to respiratory infections. Our study reports a dissociation between the systemic and the lung response to training that is probably implicated in the systemic inflammation and in the pulmonary susceptibility to infection. Copyright © 2014 by the American Thoracic Society.
Van Maele L.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1019 |
Van Maele L.,French National Center for Scientific Research |
Van Maele L.,University of Lille Nord de France |
Van Maele L.,Institute Federatif Of Recherche 142 |
And 34 more authors.
Journal of Immunology | Year: 2010
In adaptive immunity, Th17 lymphocytes produce the IL-17 and IL-22 cytokines that stimulate mucosal antimicrobial defenses and tissue repair. In this study, we observed that the TLR5 agonist flagellin induced swift and transient transcription of genes encoding IL-17 and IL-22 in lymphoid, gut, and lung tissues. This innate response also temporarily enhanced the expression of genes associated with the antimicrobial Th17 signature. The source of the Th17-related cytokines was identified as novel populations of CD3 negCD127+ immune cells among which CD4-expressing cells resembling lymphoid tissue inducer cells. We also demonstrated that dendritic cells are essential for expression of Th17-related cytokines and so for stimulation of innate cells. These data define that TLR-induced activation of CD3negCD127+ cells and production of Th17-related cytokines may be crucial for the early defenses against pathogen invasion of host tissues. Copyright © 2010 by The American Association of Immunologists, Inc.
Pichavant M.,Institute Pasteur Of Lille |
Pichavant M.,University of Lille Nord de France |
Pichavant M.,French National Center for Scientific Research |
Pichavant M.,French Institute of Health and Medical Research |
And 43 more authors.
EBioMedicine | Year: 2015
Progression of chronic obstructive pulmonary disease (COPD) is linked to episodes of exacerbations caused by bacterial infections due to Streptococcus pneumoniae. Our objective was to identify during COPD, factors of susceptibility to bacterial infections among cytokine network and their role in COPD exacerbations. S. pneumoniae was used to sub-lethally challenge mice chronically exposed to air or cigarette smoke (CS) and to stimulate peripheral blood mononuclear cells (PBMC) from non-smokers, smokers and COPD patients. The immune response and the cytokine production were evaluated. Delayed clearance of the bacteria and stronger lung inflammation observed in infected CS-exposed mice were associated with an altered production of IL-17 and IL-22 by innate immune cells. This defect was related to a reduced production of IL-1β and IL-23 by antigen presenting cells. Importantly, supplementation with recombinant IL-22 restored bacterial clearance in CS-exposed mice and limited lung alteration. In contrast with non-smokers, blood NK and NKT cells from COPD patients failed to increase IL-17 and IL-22 levels in response to S. pneumoniae, in association with a defect in IL-1β and IL-23 secretion. This study identified IL-17 and IL-22 as susceptibility factors in COPD exacerbation. Therefore targeting such cytokines could represent a potent strategy to control COPD exacerbation. © 2015 The Authors.
Ivanov S.,French Institute of Health and Medical Research |
Ivanov S.,University of Lille Nord de France |
Ivanov S.,French National Center for Scientific Research |
Ivanov S.,Institute Federatif Of Recherche 142 |
And 40 more authors.
Journal of Infectious Diseases | Year: 2012
Background.Exogenous activation of pulmonary invariant natural killer T (iNKT) cells, a population of lipid-reactive T lymphocytes, with use of mucosal -galactosylceramide (-GalCer) administration, is a promising approach to control respiratory bacterial infections. We undertook the present study to characterize mechanisms leading to -GalCer-mediated protection against lethal infection with Streptococcus pneumoniae serotype 1, a major respiratory pathogen in humans.Methods and Results.-GalCer was administered by the intranasal route before infection with S. pneumoniae. We showed that respiratory dendritic cells (DCs), most likely the CD103+ subset, play a major role in the activation (IFN-and IL-17 release) of pulmonary iNKT cells, whereas alveolar and interstitial macrophages are minor players. After challenge, S. pneumoniae was rapidly (4 hours) eliminated in the alveolar spaces, a phenomenon that depended on respiratory DCs and neutrophils, but not macrophages, and on the early production of both IFN-and IL-17. Protection was also associated with the synthesis of various interferon-dependent and IL-17-associated genes as revealed by transcriptomic analysis.Conclusions.These data imply a new function for pulmonary CD103+ DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae. © The Author 2012.
Bialecki E.,Institute Pasteur Of Lille |
Bialecki E.,University of Lille Nord de France |
Bialecki E.,French National Center for Scientific Research |
Bialecki E.,French Institute of Health and Medical Research |
And 39 more authors.
PLoS ONE | Year: 2011
One important function of conventional dendritic cells (cDC) is their high capacity to capture, process and present Ag to T lymphocytes. Mouse splenic cDC subtypes, including CD8α + and CD8α - cDC, are not identical in their Ag presenting and T cell priming functions. Surprisingly, few studies have reported functional differences between CD4 - and CD4 + CD8α - cDC subsets. We show that, when loaded in vitro with OVA peptide or whole protein, and in steady-state conditions, splenic CD4 - and CD4 + cDC are equivalent in their capacity to prime and direct CD4 + and CD8 + T cell differentiation. In contrast, in response to α-galactosylceramide (α-GalCer), CD4 - and CD4 + cDC differentially activate invariant Natural Killer T (iNKT) cells, a population of lipid-reactive non-conventional T lymphocytes. Both cDC subsets equally take up α-GalCer in vitro and in vivo to stimulate the iNKT hybridoma DN32.D3, the activation of which depends solely on TCR triggering. On the other hand, and relative to their CD4 + counterparts, CD4 - cDC more efficiently stimulate primary iNKT cells, a phenomenon likely due to differential production of co-factors (including IL-12) by cDC. Our data reveal a novel functional difference between splenic CD4 + and CD4 - cDC subsets that may be important in immune responses. © 2011 Bialecki et al.
Paget C.,Peter MacCallum Cancer Center |
Paget C.,University of Melbourne |
Paget C.,Institute Pasteur Of Lille |
Paget C.,French Institute of Health and Medical Research |
And 8 more authors.
Mucosal Immunology | Year: 2013
Mucosal sites are populated by a multitude of innate lymphoid cells and "innate-like" T lymphocytes expressing semiconserved T-cell receptors. Among the latter group, interest in type I natural killer T (NKT) cells has gained considerable momentum over the last decade. Exposure to NKT cell antigens is likely to occur continuously at mucosal sites. For this reason, and as they rapidly respond to stress-induced environmental cytokines, NKT cells are important contributors to immune and inflammatory responses. Here, we review the dual role of mucosal NKT cells during immune responses and pathologies with a particular focus on the lungs. Their role during pulmonary acute and chronic inflammation and respiratory infections is outlined. Whether NKT cells might provide a future attractive therapeutic target for treating human respiratory diseases is discussed.
Deprez-Poulain R.,Institute Pasteur Of Lille |
Deprez-Poulain R.,Institut Universitaire de France |
Deprez-Poulain R.,French Institute of Health and Medical Research |
Deprez-Poulain R.,Institute Federatif Of Recherche 142 |
And 87 more authors.
Nature Communications | Year: 2015
Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes. © 2015 Macmillan Publishers Limited. All rights reserved.
Paget C.,French Institute of Health and Medical Research |
Paget C.,University of Lille Nord de France |
Paget C.,French National Center for Scientific Research |
Paget C.,Institute Federatif Of Recherche 142 |
And 36 more authors.
Journal of Biological Chemistry | Year: 2012
Invariant natural killer T (iNKT) cells are non-conventional lipid-reactive αβ T lymphocytes that play a key role in host responses during viral infections, in particular through the swift production of cytokines. Their beneficial role during experimental influenza A virus (IAV) infection has recently been proposed, although the mechanisms involved remain elusive. Here we show that during in vivo IAV infection, mouse pulmonary iNKT cells produce IFN-γ and IL-22, a Th17-related cytokine critical in mucosal immunity. Although permissive to viral replication, IL-22 production by iNKT cells is not due to IAV infection per se of these cells but is indirectly mediated by IAV-infected dendritic cells (DCs). We show that activation of the viral RNA sensors TLR7 and RIG-I in DCs is important for triggering IL-22 secretion by iNKT cells, whereas the NOD-like receptors NOD2 and NLRP3 are dispensable. Invariant NKTcells respond to IL-1β and IL-23 provided by infected DCs independently of the CD1d molecule to release IL-22. In vitro, IL-22 protects IAV-infected airway epithelial cells against mortality but has no role on viral replication. Finally, during early IAV infection, IL-22 plays a positive role in the control of lung epithelial damages. Overall, IAV infection of DCs activates iNKT cells, providing a rapid source of IL-22 that might be beneficial to preserve the lung epithelium integrity. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Renneson J.,Institute Pasteur Of Lille |
Renneson J.,University of Lille Nord de France |
Renneson J.,French National Center for Scientific Research |
Renneson J.,French Institute of Health and Medical Research |
And 31 more authors.
American Journal of Pathology | Year: 2011
Dengue virus (DENV), a member of the mosquito-borne flaviviruses, is a serious public health problem in many tropical countries. We assessed the in vivo physiologic contribution of invariant natural killer T (iNKT) cells, a population of nonconventional lipid-reactive αβ T lymphocytes, to the host response during experimental DENV infection. We used a mouse-adapted DENV serotype 2 strain that causes a disease that resembles severe dengue in humans. On DENV challenge, splenic and hepatic iNKT cells became activated insofar as CD69 and Fas ligand up-regulation and interferon-γ production. C57BL/6 mice deficient in iNKT cells (Jα18 -/-) were more resistant to lethal infection than were wild-type animals, and the phenotype was reversed by adoptive transfer of iNKT cells to Jα18 -/- animals. The absence of iNKT cells in Jα18 -/- mice was associated with decreased systemic and local inflammatory responses, less liver injury, diminished vascular leak syndrome, and reduced activation of natural killer cells and neutrophils. iNKT cell functions were not necessary for control of primary DENV infection, after either natural endogenous activation or exogenous activation with the canonical iNKT cell agonist α-galactosylceramide. Together, these data reveal a novel and critical role for iNKT cells in the pathogenesis of severe experimental dengue disease. © 2011 American Society for Investigative Pathology.
Dieudonne A.,Institute Pasteur Of Lille |
Dieudonne A.,University of Lille Nord de France |
Dieudonne A.,French National Center for Scientific Research |
Dieudonne A.,French Institute of Health and Medical Research |
And 35 more authors.
PLoS ONE | Year: 2012
Scavenger receptors and Toll-like receptors (TLRs) cooperate in response to danger signals to adjust the host immune response. The TLR3 agonist double stranded (ds)RNA is an efficient activator of innate signalling in bronchial epithelial cells. In this study, we aimed at defining the role played by scavenger receptors expressed by bronchial epithelial cells in the control of the innate response to dsRNA both in vitro and in vivo. Expression of several scavenger receptor involved in pathogen recognition was first evaluated in human bronchial epithelial cells in steady-state and inflammatory conditions. Their implication in the uptake of dsRNA and the subsequent cell activation was evaluated in vitro by competition with ligand of scavenger receptors including maleylated ovalbumin and by RNA silencing. The capacity of maleylated ovalbumin to modulate lung inflammation induced by dsRNA was also investigated in mice. Exposure to tumor necrosis factor-α increased expression of the scavenger receptors LOX-1 and CXCL16 and the capacity to internalize maleylated ovalbumin, whereas activation by TLR ligands did not. In contrast, the expression of SR-B1 was not modulated in these conditions. Interestingly, supplementation with maleylated ovalbumin limited dsRNA uptake and inhibited subsequent activation of bronchial epithelial cells. RNA silencing of LOX-1 and SR-B1 strongly blocked the dsRNA-induced cytokine production. Finally, administration of maleylated ovalbumin in mice inhibited the dsRNA-induced infiltration and activation of inflammatory cells in bronchoalveolar spaces and lung draining lymph nodes. Together, our data characterize the function of SR-B1 and LOX-1 in bronchial epithelial cells and their implication in dsRNA-induced responses, a finding that might be relevant during respiratory viral infections. © 2012 Dieudonné et al.