Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The development of inflammatory granulomas around infected Kupffer cells is necessary for hepatic parasite clearance during visceral leishmaniasis. Invariant NKT (iNKT) cells are predominant T cells in the mouse liver and can synthesize large quantities of IL-4 and IFN-γ, two cytokines involved in granuloma formation. This study analyzed the role of iNKT cells in the hepatic immune response during Leishmania donovani infection, using a murine model of wild-type (WT) and iNKT cell-deficient (Jα18⁻/⁻) C57BL/6 mice sacrificed 15, 30 or 60 days post-infection. We recorded hepatic parasite loads, cytokine expression, and analyzed granulomatous response by immunohistochemistry and hepatic immune cell infiltration by flow cytometry. Whereas WT animals rapidly controlled the infection and developed an inflammatory response associated with a massive influx of iNKT cells observed by flow cytometry, Jα18⁻/⁻ mice had significantly higher parasitic loads on all time points. This lack of control of parasite burden was associated with a delay in granuloma maturation (28.1% of large granulomas at day 60 versus 50.7% in WT). Cytokine transcriptome analysis showed that mRNA of 90/101 genes encoding chemokines, cytokines and their receptors, was underexpressed in Jα18⁻/⁻ mice. Detection of IL-4 and TNF-α by ELISA in liver extracts was also significantly lower in Jα18⁻/⁻ mice. Consistent with flow cytometry analysis, cytokinome profile in WT mice showed a bias of expression towards T cell-chemoattractant chemokines on D15, and displayed a switch towards expression of granulocytes and/or monocytes -chemoattractant chemokines on D60. In Jα18⁻/⁻ mice, the significantly lower expression of CXCL5, MIP-2 and CCL2 mRNA was correlated with a defect in myeloperoxidase positive-cell attraction observed by immunohistochemistry and with a lower granulocyte and monocyte infiltration in the liver, as shown by flow cytometry. These data indicate that iNKT cells play a role in early and sustained pro-inflammatory cytokine response warranting efficient organization of hepatic granulomas and parasite clearance.
ISSN: 1932-6203

hal-00696897
https://hal.archives-ouvertes.fr/hal-00696897
https://hal.archives-ouvertes.fr/hal-00696897/document
https://hal.archives-ouvertes.fr/hal-00696897/file/Invariant_NKT_Cells_Drive-accepted.pdf
DOI : 10.1371/journal.pone.0033413

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Interleukin-27 (IL-27) belongs to the IL-6/IL-12 family of cytokines, associated with different inflammatory diseases and orchestrates its biological activity via common heterodimeric receptor composed of WSX-1 (IL-27Rα) and gp130. The present study was aimed to investigate the regulation of CXCL9, CXCL10, and CXCL11 chemokines in hepatic cells (human LX-2 cell line derived from normal human stellate cells (HSC), primary human hepatocytes, HSC, and HepG2 cells) and concanavalin A (ConA)-induced liver inflammation. We demonstrated that IL-27, but not IL-6, induced/up-regulated CXCR3 ligand genes (CXCL9, CXCL10, and CXCL11; out of 26 selected genes) in a STAT1-dependent manner in hepatic cells in vitro both at transcript and protein levels. In ConA-induced T cell-mediated hepatic model, we showed that soluble IL-27/IFNγ was elevated following ConA hepatitis in association with increased CXCL9, CXCL10, and CXCL11 expression in the liver. The exogenous IL-27 administration induced CXCR3 ligands in mouse liver at 4 h with any significant effect on recruitment of CXCR3(+) immune cells in the liver. The neutralization of IL-27 during ConA hepatitis differentially modulated (transcript vs protein expression) CXCR3 ligands and IFNγ during ConA-induced hepatitis with down-regulated expression of CXCL9 and CXCL10 at transcript level. The IFNγ, complementary regulated the expression of CXCR3 ligands as their up-regulation during ConA hepatitis, was abolished in IFNγ KO mice. In summary, IL-27 up-regulated the CXCL9, CXCL10, and CXCL11 chemokine expression in hepatic cells. IL-27 regulated CXCR3 ligand expression in IFNγ-dependent manner during acute hepatitis suggesting a complementary role of IL-27 and IFNγ to moderate liver inflammation via regulation of CXCR3 ligands. KEY MESSAGE: IL-27 up-regulated CXCR3 ligand expression in human hepatic cells in vitro. IL-27 up-regulated CXCR3 ligand expression and secretion in ConA hepatitis in vivo. CXCR3 ligand expression was down-regulated by blocking IL-27 or IFNγ deficiency. IL-27 modulated liver injury by regulation of CXCR3 ligands in IFNγ-dependent manner.
ISSN: 0946-2716

hal-01214006
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01214006
DOI : 10.1007/s00109-015-1319-6
PUBMED : 26199110

Éditeur(s) : HAL CCSD
Résumé : International audience
Acute viral hepatitis results from an inefficient innate immune response to clear the virus and a delayed immune adaptive response. Murine hepatitis virus (MHV) infection represents a unique animal model to identify new escape mechanisms in liver of innate immune responses. The objective of this study was to identify early disorders in TLRs, helicases, cytokines and chemokines favoring the development of a fulminant hepatitis. Groups of C57BL/6 WT and TLR2-/- mice were infected with highly hepatotropic MHV3 and/or weakly hepatotropic MHV-A59 viruses. Histopathological analysis of liver and mRNA expression levels of viral nucleoprotein, viral sensors, interferons, cytokines and chemokines assessed by RT-qPCR were done in the first 3 days of infection. The results showed that liver damages, viral replication and mRNA levels of TLR-2, TLR-3, RIG-1, MDA-5, IL-33, IFN-b, CXCL1, CXCL9, CXCL-10, CXCL-11, CCL3, CCL5, IL-6 and TNF-a increased higher or appeared sooner in MHV3-infected WT than in MHV-A59 and TLR2-/- mice. To address the role of hepatocytes in TLR2-dependent viral replication and innate immune factors, in vitro viral infections were performed on FL83B cells. The results showed that viral replication and mRNA levels of TLR-2 and IL-6 occurred sooner than those of other innate immune parameters. Moreover, blockade of TLR-2 by siRNA decreased IFN-b, TNF-a, CXCL-1, CXCL-10 and CCL-2 expression in infected hepatocytes and also inhibited the viral replication of MHV-A59, and at a lesser extent of MHV3, suggesting that TLR-2 signaling promotes simultaneously the viral replication and the production of innate immune factors in hepatocytes, exacerbating viral hepatitis.
Frontiers of Immunology
Milan, Italy

hal-01118155
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118155
DOI : 10.3389/conf.fimmu.2013.02.00648

Éditeur(s) : HAL CCSD Federation of American Society of Experimental Biology
Résumé : International audience
The innate immune system is able to detect bacterial LPS through the pattern recognition receptor CD14, which delivers LPS to various TLR signaling complexes that subsequently induce intracellular proinflammatory signaling cascades. In a previous study, we showed the overproduction of the soluble form of CD14 (sCD14) by macrophages from patients with cystic fibrosis (CF). CF is an autosomal recessive disorder that is caused by mutations in the gene that encodes the CFTR protein and is characterized by persistent inflammation. Macrophages play a significant role in the initial stages of this disease due to their inability to act as suppressor cells, leading to chronic inflammation in CF. In this work, we investigated the origin of sCD14 by human macrophages and studied the effect of sCD14 on the production of inflammatory cytokine/chemokine. Our data indicate that sCD14 stimulate proinflammatory cytokine/chemokine production in a manner that is independent of LPS but dependent on the TLR-4/CD14 membrane complex, NF-κB, and the inflammasome. Therefore, sCD14, overproduced by CF macrophages, originates primarily from the endocytosis/exocytosis process and should be considered to be a danger-associated molecular pattern. This elucidation of the origin and inflammation-induced mechanisms associated with sCD14 contributes to our understanding of maintained tissue inflammation.
ISSN: 0892-6638

hal-01526434
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526434
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526434/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526434/file/Soluble%20CD14%20acts%20as%20a%20DAMP%20in%20human-accepted.pdf
PUBMED : 28122919

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Monocytes/macrophages (MΦ), considered as plastic cells, can differentiate into either a pro-inflammatory (M1) subtype, also known as a classically activated subtype, or an anti-inflammatory alternatively activated subtype (M2) according to their microenvironment. Phenotypic markers of mouse polarized MΦ have been extensively studied, whereas their human counterparts remain less characterized. The main goal of this study was therefore to carefully characterize phenotypic and genomic markers of primary human MΦ generated from M-CSF-treated blood monocytes and polarized towards M1 or M2 subtype upon the action of lipopolysaccharide and interferon-γ (for M1) or interleukin (IL)-4 (for M2). Membrane expression of the markers CD80 and CD200R was found to be specific of human M1 and M2 polarized MΦ, respectively, whereas, by contrast, mannose receptor (CD206) expression did not discriminate between M1 and M2. mRNA expression analysis further identified six markers of M1 polarization (IL-12p35, CXCL10, CXCL11, CCL5, CCR7 and IDO1), five markers of M2 polarization (TGF-β, CCL14, CCL22, SR-B1 and PPARγ) and transcription factors involved in MΦ polarization. Ability of human M-CSF-generated MΦ to polarize toward M1 or M2 subtype was also associated with enhanced secretion of TNFα, IL-1β, IL-12p40, CXCL10 and IL-10 (for M1) or CCL22 (for M2). Moreover, the comparison of the expression of M1 markers in M-CSF- and GM-CSF-MΦ polarized towards M1 subtype has revealed similarities. In conclusion, we demonstrated that human M-CSF MΦ can polarize toward a M1 type after IFNγ/LPS stimulation. Moreover, the M1 and M2 markers of human polarized MΦ identified in the present study may be useful to better identify human MΦ subtypes, particularly at the tissue level, in order to better understand their respective roles in the development of pathologies.
ISSN: 0008-8749

inserm-00823273
http://www.hal.inserm.fr/inserm-00823273
DOI : 10.1016/j.cellimm.2013.01.010
PUBMED : 23454681

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
UNLABELLED: During visceral leishmaniasis, the control of hepatic parasite burden is mainly due to granuloma assembly in a microenvironment consisting of both Th1 and Th2 components. Using enzyme-linked immunosorbent assay (ELISA) dosages, quantitative PCR (qPCR), immunohistochemistry, and flow cytometry, we studied the role of interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, during visceral leishmaniasis. We showed that a higher level of IL-33 was detected in the serum of patients with visceral leishmaniasis than in that from healthy donors and demonstrated the presence of IL-33(+) cells in a liver biopsy specimen from a patient. Similarly, in BALB/c mice experimentally infected with L. donovani, a higher level of IL-33 was detected in the serum, as well as the presence of IL-33(+) cells and ST2(+) cells in the mouse liver. In ST2(-/-) BALB/c mice, better control of the hepatic parasite burden and reduced hepatomegaly were observed. This was associated with strong induction of Th1 cytokines (gamma interferon [IFN-γ] and IL-12) compared to the level in wild-type (WT) mice and better recruitment of myeloid cells associated with strongly induced chemokines (CCL2 and CXCL2) and receptors (CCR2 and CXCR2). Conversely, BALB/c mice treated twice weekly with recombinant IL-33 showed a dramatically reduced induction of Th1 cytokines and delayed inhibition of monocyte and neutrophil recruitment in the liver, which was associated with reduced KC/CXCL1 and CXCR2 expression. Taken together, our results suggest that IL-33 could be a new deleterious regulator of the hepatic immune response against Leishmania donovani, via the repression of the Th1 response and myeloid cell recruitment. IMPORTANCE: Visceral leishmaniasis is a life-threatening systemic disease due to the Leishmania protozoa L. infantum and L. donovani and is ranked by the World Health Organization as the second most important protozoan parasitic disease after malaria for its grave morbidity, high mortality, and global distribution. Leishmania parasites subvert the host's immune response to propagate to target organs, including the spleen, the bone marrow, and the liver. Control of hepatic parasite burdens depends on a delicate and poorly understood Th1/Th2 immune balance. To better understand this complex immune response, new cytokines are interesting targets for research studies. IL-33 is a newly described cytokine usually associated with Th2 response and involved in different diseases, including infectious diseases and hepatitis. Our results suggest that IL-33 could be a new factor of susceptibility and a potential prognostic marker during visceral leishmaniasis.
ISSN: 2150-7511

inserm-00871493
http://www.hal.inserm.fr/inserm-00871493
http://www.hal.inserm.fr/inserm-00871493/document
http://www.hal.inserm.fr/inserm-00871493/file/mBio.00383-13.pdf
DOI : 10.1128/mBio.00383-13

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC.
ISSN: 0300-483X

hal-00682486
https://hal.archives-ouvertes.fr/hal-00682486
DOI : 10.1016/j.tox.2011.11.011
PUBMED : 22138297

Éditeur(s) : HAL CCSD
Résumé : Macrophages (MΦ), well-known to play a key role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP), an air pollutant recently classified as carcinogenic to humans. MΦ are heterogeneous and plastic cells which activate according to their microenvironment into either an M1 subtype (so called classically activated or pro-inflammatory) under IFNγ and LPS stimulation or an M2 subtype (so called alternatively activated or anti-inflammatory) under IL-4 and/or IL-13 stimulation. However, potential effects of DEPs on M1/M2 MΦ polarization remain poorly documented. First, we characterized the expression marker of in vitro M-CSF-differentiated MΦ from human monocytes and activated into the M1 or M2 subtypes. Our main results show that M-CSF-generated MΦ considered as anti-inflammatory are actually able to switch to an M1 phenotype after IFNγ/LPS stimulation. Furthermore, the markers identified in this study were used to assess the impact of organic extracts of DEP (DEPe) on MΦ polarization and more generally on their physiology. DEPe alter some M1 and M2 markers expressed by polarized MΦ, without causing the overall inhibition of the M1 and M2 polarization process or the switch to a different phenotype. This phenotype alteration is associated with a decrease in the LPS-dependent inflammatory response in M1 MΦ and the chemotactic capacities in M2 MΦ. DEPe decrease the secretion of some cytokines and chemokines such as IL-6, IL-12p40 and CCL18 via AhR and/or Nrf2 activation. At the same time, we show that M1 and M2 MΦ in response to DEPe are able to secrete a sufficient level of a pro-fibrotic growth factor, the platelet derived growth factor B (PDGF-B) via AhR activation, leading to stimulation of lung fibroblast proliferation. Finally, these works show that DEPe have immunotoxic properties with regards to the physiology of human in vitro polarized MΦ. This immunotoxicity may then contribute to the deleterious effects of these urban environmental contaminants on human health.
Les macrophages (MΦ), des cellules clefs de la réponse immunitaire peuvent répondre à des contaminants environnementaux comme les particules diesel (DEP), des polluants atmosphériques récemment classés cancérigènes pour l'Homme. Les MΦ sont des cellules hétérogènes et plastiques qui s'activent en fonction de leur microenvironnement soit en MΦ M1 (dits classiquement activés ou pro-inflammatoires) sous l'effet de l'INFγ et du LPS soit en MΦ M2 (dits alternativement activés ou réparateurs) sous l'effet de l'IL-4 et/ou de l'IL-13. Les effets des DEP sur la polarisation M1/M2 des MΦ restent peu documentés. Nous avons dans un premier temps caractérisé l'expression des marqueurs des MΦ différenciés in vitro en présence de M-CSF à partir de monocytes humains et polarisés en sous-type M1 ou M2. Nos principaux résultats montrent que les MΦ différenciés au M-CSF considérés comme des MΦ anti-inflammatoires, sont en réalité capables de s'activer vers un phénotype M1 après une stimulation au LPS/IFNγ. De plus, les marqueurs mis en évidence au cours de ce travail ont permis d'évaluer l'impact d'extraits organiques de DEP (DEPe) sur la polarisation des MΦ et plus généralement sur leur physiologie. Les DEPe altèrent l'expression de certains marqueurs M1 et M2 des MΦ, sans toutefois provoquer d'inhibition globale des processus de polarisation M1 et M2 ou de transition d'un phénotype vers un autre. Cette altération du phénotype est associée à une diminution de la réponse inflammatoire LPS-dépendante dans les MΦ M1 et des capacités chimiotactiques des MΦ M2. Les DEPe diminuent la sécrétion de certaines cytokines et chimiokines comme l'IL-6, l'IL-12p40 et le CCL18 via l'activation d'AhR et/ou de Nrf2. Parallèlement, nous montrons que les MΦ M1 et M2 exposés aux DEPe sécrètent le platelet deried growth factor B (PDGF-B), un facteur de croissance profibrosant, via l'activation d'AhR en quantité suffisante pour stimuler la prolifération de fibroblastes pulmonaires. Au total, ces travaux démontrent que les DEP possèdent des propriétés immunotoxiques vis-à-vis de la physiologie des macrophages humains polarisés in vitro. Cette immunotoxicité pourrait participer aux effets délétères de ces contaminants environnementaux urbains sur la santé humaine.
https://tel.archives-ouvertes.fr/tel-01188679

NNT : 2015REN1S011
tel-01188679
https://tel.archives-ouvertes.fr/tel-01188679
https://tel.archives-ouvertes.fr/tel-01188679/document
https://tel.archives-ouvertes.fr/tel-01188679/file/JAGUIN_Marie.pdf

Éditeur(s) : HAL CCSD Taylor & Francis
Résumé : International audience
INTRODUCTION: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for regulating expression of several important drug-detoxifying proteins. Besides drug metabolism pathways, cytokines have been recently recognized as targeted by the AhR signaling cascade, which may contribute to toxicity and changes in xenobiotic detoxification caused by AhR agonists. AREAS COVERED: This article summarizes the nature of the main cytokines regulated by AhR ligands and reviews their involvement in toxic effects of AhR ligands, especially in relation with inflammation. The article also discusses the potential implications for drug detoxification pathways. EXPERT OPINION: Even if various cytokines, including inflammatory ones, have already been demonstrated to constitute robust targets for AhR, the exact role played by AhR with respect to inflammation remains to be determined. Further studies are also required to better characterize the molecular mechanisms implicated in regulation of cytokines by AhR ligands and to determine the role that may play AhR-targeted cytokines in alteration of xenobiotic detoxification. Finally, changes in cytokine receptor expression triggered by AhR ligands have additionally to be taken into account to better and more extensively comprehend the role played by AhR in the cytokine/inflammation area.
ISSN: 1742-5255

inserm-00831662
http://www.hal.inserm.fr/inserm-00831662
DOI : 10.1517/17425255.2013.738194
PUBMED : 23230817

Éditeur(s) : HAL CCSD
Résumé : Visceral leishmaniasis is a life-threatening systemic disease caused by Leishmania protozoans, L. donovani and L. infantum, which invade mononuclear phagocytes in the lymphoid organs and the liver. The control of the hepatic parasite burden depends on the granuloma formation, which is favored by a Th1 immune response in a Th2 tissue microenvironment. The aim of this work was to study the role of the recently described Th2 cytokine IL-33 in this complex immune response, which remains partially misunderstood. IL-33 dosages in different patient sera and IL-33+ cells detected in the liver of a patient from Rennes suggested that IL-33 could be a biomarker for active visceral leishmaniasis. As IL-33 was described in hepatic stellate cells during chronic hepatitis, these cells were exposed to L. donovani in primary culture. The cell permissivity to L. donovani and the parasite persistence during a long term culture led us to propose hepatic stellate cells as a new type of sanctuary cells, which could partially explain asymptomatic carriage. However, these cells were apparently not the main source of IL-33 during visceral leishmaniasis. In infected BALB/c and C57BL/6 mice, IL-33 was detected in the liver in non stellate cells preferentially localized in granulomas. The presence of cells expressing its specific receptor ST2 in the liver led us to explore the role of the IL-33/ST2 axis. BALB/c mice deficient in ST2 or treated with recombinant IL-33 and infected with L. donovani revealed that IL-33 downregulates the expression of Th1 key cytokines (IL-12, IFN-γ) and the recruitment of neutrophils and monocytes. Finally, IL-33 acts as a susceptibility factor during visceral leishmaniasis. Besides, the model of L. donovani infected C57BL/6 mice deficient in IL-33 or treated with recombinant IL-33 suggests possible differential roles of IL-33 depending on the immune environment related to the host genetic background.
La leishmaniose viscérale est une maladie systémique mortelle en l’absence de traitement. Elle est due aux protozoaires Leishmania donovani et L. infantum, parasites des phagocytes mononucléés, capables d’envahir les organes lymphoïdes et le foie. Le contrôle de l’infection hépatique repose sur la mise en place d’une réponse granulomateuse efficace, promue par une réponse immunitaire Th1, dans un environnement tissulaire Th2. L’objectif de ce travail était l'étude du rôle d’une cytokine Th2 récemment décrite, l’IL-33, dans cette réponse hépatique complexe encore partiellement incomprise. Des dosages d’IL-33 sur des sérums de patients et la détection de cellules IL-33+ dans le foie d’un patient rennais ont placé l’IL-33 comme un biomarqueur possible de la maladie active. L’IL-33 étant exprimée dans les cellules étoilées du foie au cours d’hépatites chroniques, ces cellules ont été exposées à L. donovani. Leur permissivité aux leishmanies sans toxicité apparente ni perturbation de leurs propriétés fonctionnelles, ainsi que la persistance des leishmanies sur une culture de plusieurs semaines, nous ont conduit à proposer les cellules étoilées comme cellules sanctuaires possibles pour les leishmanies viscérotropes, contribuant donc potentiellement au portage asymptomatique. En revanche, elles ne sont pas apparues comme une source majeure d'IL-33 au cours de la leishmaniose viscérale. Chez des souris C57BL/6 et BALB/c infectées par L. donovani, l'IL-33 a été observée dans des cellules ne s'apparentant pas à des cellules étoilées, et principalement localisées dans les granulomes. Des cellules exprimant son récepteur ST2 ayant été également observées dans le foie, un rôle de l’axe IL-33/ST2 a été recherché. Les résultats obtenus chez des souris BALB/c déficientes en ST2 ou traitées par de l'IL-33 recombinante suggèrent que l'IL-33 régule négativement l'expression de cytokines Th1 (IL-12, IFN-γ) et l'infiltrat de neutrophiles et monocytes dans le foie, limitant ainsi le contrôle de la charge parasitaire. Ainsi, l'IL-33 semble être un facteur de susceptibilité pour la leishmaniose viscérale. En parallèle, des travaux entrepris sur des souris C57BL/6 infectées par L. donovani suggèrent de possibles rôles différentiels de l'IL-33 en fonction de l'environnement immunitaire inhérent au fond génétique de l'hôte.
https://tel.archives-ouvertes.fr/tel-01126847

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2013REN1B002
tel-01126847
https://tel.archives-ouvertes.fr/tel-01126847
https://tel.archives-ouvertes.fr/tel-01126847/document
https://tel.archives-ouvertes.fr/tel-01126847/file/2013REN1B002.pdf

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
Coronaviruses (CoVs) have shown neuroinvasive properties in human and animal secondary to replication in peripheral organ but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood brain barrier (BBB). Using the high hepatotropic mouse hepatitis virus (MHV) type 3, its attenuated variant 51.6-MHV3, showing low tropism for endothelial cells, and the low hepatotropic MHV-A59 strains from murine coronavirus group, we investigated the viral-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was only observed in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of ZO-1, VE-cadherin and occludin but not claudin-5 in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective IFN-β production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCE: Coronaviruses (CoVs) infect several mammals including humans and are associated with respiratory, gastrointestinal and/or neurological diseases. Some evidences suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the SARS-CoV, causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS and multiple sclerosis patients respectively. These finding suggest that hematogenous spread CoVs may gain access to CNS at the BBB level. Herein we report for the first time that CoVs exhibit ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with viral-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion
ISSN: 0022-538X

hal-01187308
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187308
DOI : 10.1128/JVI.01501-15
PUBMED : 26202229