Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL-33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33.
ISSN: 1932-6203

hal-00874120
https://hal.archives-ouvertes.fr/hal-00874120
https://hal.archives-ouvertes.fr/hal-00874120/document
https://hal.archives-ouvertes.fr/hal-00874120/file/Pathogenic_Mouse_Hepatitis-accepted.pdf
DOI : 10.1371/journal.pone.0074278

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance toward self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or Toll-like receptor 2 (TLR2) activation, LSECs can achieve proinflammatory functions, but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus type 3 (MHV3) and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their proinflammatory profiles and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, and levels of inflammatory mediators and earlier recruitment of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of interleukin-10 (IL-10) and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of proinflammatory and procoagulant factors and earlier cell damage than infection by attenuated strains. This higher replication and proinflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signaling by the virus. We provide evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of the immunotolerant properties of LSECs during acute viral hepatitis is imperative in order to limit hepatic inflammation and damage. IMPORTANCE Viral hepatitis B and C infections are serious health problems affecting over 350 million and 170 million people worldwide, respectively. It has been suggested that a balance between protection and liver damage mediated by the host's immune response during the acute phase of infection would be determinant in hepatitis outcome. Thus, it appears crucial to identify the factors that predispose in exacerbating liver inflammation to limit hepatocyte injury. Liver sinusoidal endothelial cells (LSECs) can express both anti- and proinflammatory functions, but their role in acute viral hepatitis has never been investigated. Using mouse hepatitis virus (MHV) infections as animal models of viral hepatitis, we report for the first time that in vitro and in vivo infection of LSECs by the pathogenic MHV3 serotype leads to a reversion of their intrinsic anti-inflammatory phenotype toward a proinflammatory profile as well to as disorders in vascular factors, correlating with the severity of hepatitis. These results highlight a new virus-promoted mechanism of exacerbation of liver inflammatory response during acute hepatitis.
ISSN: 0022-538X

hal-01390974
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390974
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390974/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390974/file/Mouse%20Hepatitis%20Virus%20Infection_accepted.pdf
DOI : 10.1128/JVI.01069-16

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Whereas it is well established that prenatal exposure to polychlorinated biphenyls (PCBs) can disrupt children's behavior, early postnatal exposure has received relatively little attention in environmental epidemiology. To evaluate prenatal and postnatal exposures to PCB-153, a proxy of total PCB exposure, and their relation to inattention and activity in 5-year-old Inuits from the Cord Blood Monitoring Program. Prenatal exposure to PCBs was informed by cord plasma PCB-153 levels. We used a validated pharmacokinetic model to estimate monthly infants' levels across the first year of life. Inattention and activity were assessed by coding of video recordings of children undergoing fine motor testing. We used multivariable linear regression to evaluate the association between prenatal and postnatal PCB-153 levels and inattention (n=97) and activity (n=98) at 5years of age. Cord plasma PCB-153 was not associated with inattention and activity. Each interquartile range (IQR) increase in estimated infant PCB-153 levels at 2months was associated with a 1.02% increase in the duration of inattention (95% CI: 0.04, 2.00). Statistical adjustment for the duration of breastfeeding slightly increased regression coefficients for postnatal level estimates, some of which became statistically significant for inattention (months: 2-4) and activity (months: 2-5). Our study adds to the growing evidence of postnatal windows of development during which children are more susceptible to neurotoxicants like PCBs.
ISSN: 0160-4120

hal-01134338
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134338
DOI : 10.1016/j.envint.2015.02.004
PUBMED : 25796081

Éditeur(s) : HAL CCSD
Résumé : International audience
The alarmin IL-33 has been described to be upregulated in human and murine viral hepatitis. However, the role of endogenous IL-33 in viral hepatitis remains obscure. We aimed to decipher its function by infecting IL-33-deficient mice (IL-33 KO) and their wild-type (WT) littermates with pathogenic mouse hepatitis virus (L2-MHV3). The IL-33 KO mice were more sensitive to L2-MHV3 infection exhibiting higher levels of AST/ALT, higher tissue damage, significant weight loss, and earlier death. An increased depletion of B and T lymphocytes, NKT cells, dendritic cells, and macrophages was observed 48 h postinfection (PI) in IL-33 KO mice than that in WT mice. In contrast, a massive influx of neutrophils was observed in IL-33 KO mice at 48 h PI. A transcriptomic study of inflammatory and cell-signaling genes revealed the overexpression of IL-6, TNFα, and several chemokines involved in recruitment/activation of neutrophils (CXCL2, CXCL5, CCL2, and CCL6) at 72 h PI in IL-33 KO mice. However, the IFNγ was strongly induced in WT mice with less profound expression in IL-33 KO mice demonstrating that endogenous IL-33 regulated IFNγ expression during L2-MHV3 hepatitis. In conclusion, we demonstrated that endogenous IL-33 had multifaceted immunoregulatory effect during viral hepatitis via induction of IFNγ, survival effect on immune cells, and infiltration of neutrophils in the liver.
Mediators of Inflammation

hal-01544268
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01544268
DOI : 10.1155/2017/1359064
PUBMED : 28607531
PUBMEDCENTRAL : PMC5457781

Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences
Résumé : International audience
Background: Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern between prenatal and postnatal effects.Objectives: We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity).Methods: We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p,p´-dichlorodiphenyldichloroethylene (p,p´-DDE) (n = 1,864), estimating prenatal and postnatal POPs exposure using a validated pharmacokinetic model. Growth was change in weight-for-age z-score between birth and 24 months. Per compound, multilevel models were fitted with either POPs total exposure from conception to 24 months or prenatal or postnatal exposure.Results: We found a significant increase in growth associated with p,p´-DDE, seemingly due to prenatal exposure (per interquartile increase in exposure, adjusted β = 0.12; 95% CI: 0.03, 0.22). Due to heterogeneity across cohorts, this estimate cannot be considered precise, but does indicate that an association with infant growth is present on average. In contrast, a significant decrease in growth was associated with postnatal PCB-153 exposure (β = –0.10; 95% CI: –0.19, –0.01).Conclusion: To our knowledge, this is the largest study to date of POPs exposure and infant growth, and it contains state-of-the-art exposure modeling. Prenatal p,p´-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels.
ISSN: 0091-6765

hal-01196597
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01196597
DOI : 10.1289/ehp.1308005
PUBMED : 25742056

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
Résumé : International audience
Viral replication in the liver is generally detected by cellular endosomal Toll-like receptors (TLRs) and cytosolic helicase sensors that trigger antiviral inflammatory responses. Recent evidence suggests that surface TLR2 may also contribute to viral detection through recognition of viral coat proteins but its role in the outcome of acute viral infection remains elusive. In this study, we examined in vivo the role of TLR2 in acute infections induced by the highly hepatotrophic mouse hepatitis virus (MHV) type 3 and weakly hepatotrophic MHV-A59 serotype. To address this, C57BL/6 (wild-type; WT) and TLR2 knockout (KO) groups of mice were intraperitoneally infected with MHV3 or MHV-A59. MHV3 infection provoked a fulminant hepatitis in WT mice, characterized by early mortality and high alanine and aspartate transaminase levels, histopathological lesions and viral replication whereas infection of TLR2 KO mice was markedly less severe. MHV-A59 provoked a comparable mild and subclinical hepatitis in WT and TLR2 KO mice. MHV3-induced fulminant hepatitis in WT mice correlated with higher hepatic expression of interferon-β, interleukin-6, tumour necrosis factor-α, CXCL1, CCL2, CXCL10 and alarmin (interleukin-33) than in MHV-A59-infected WT mice and in MHV3-infected TLR2 KO mice. Intrahepatic recruited neutrophils, natural killer cells, natural killer T cells or macrophages rapidly decreased in MHV3-infected WT mice whereas they were sustained in MHV-A59-infected WT mice and MHV3-infected TLR2 KO. MHV3 in vitro infection of macrophagic cells induced rapid and higher viral replication and/or interleukin-6 induction in comparison to MHV-A59, and depended on viral activation of TLR2 and p38 mitogen-activated protein kinase. Taken together, these results support a new aggravating inflammatory role for TLR2 in MHV3-induced acute fulminant hepatitis. © 2016 John Wiley & Sons Ltd
Immunology

Droits : info:eu-repo/semantics/OpenAccess
hal-01373946
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01373946
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01373946/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01373946/file/Toll-like%20receptor%20%28tlr%29-2%20exacerbates%20murine%20acute%20viral%20hepatitis.pdf
DOI : 10.1111/imm.12627

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

Éditeur(s) : HAL CCSD Ecological Society of America
Résumé : CABI:20153174020
Understanding how plants are constructed - i.e., how key size dimensions and the amount of mass invested in different tissues varies among individuals - is essential for modeling plant growth, carbon stocks, and energy fluxes in the terrestrial biosphere. Allocation patterns can differ through ontogeny, but also among coexisting species and among species adapted to different environments. While a variety of models dealing with biomass allocation exist, we lack a synthetic understanding of the underlying processes. This is partly due to the lack of suitable data sets for validating and parameterizing models. To that end, we present the Biomass And Allometry Database (BAAD) for woody plants. The BAAD contains 259634 measurements collected in 176 different studies, from 21084 individuals across 678 species. Most of these data come from existing publications. However, raw data were rarely made public at the time of publication. Thus, the BAAD contains data from different studies, transformed into standard units and variable names. The transformations were achieved using a common workflow for all raw data files. Other features that distinguish the BAAD are: (i) measurements were for individual plants rather than stand averages; (ii) individuals spanning a range of sizes were measured; (iii) plants from 0.01-100 m in height were included; and (iv) biomass was estimated directly, i.e., not indirectly via allometric equations (except in very large trees where biomass was estimated from detailed sub-sampling). We included both wild and artificially grown plants. The data set contains the following size metrics: total leaf area; area of stem cross-section including sapwood, heartwood, and bark; height of plant and crown base, crown area, and surface area; and the dry mass of leaf, stem, branches, sapwood, heartwood, bark, coarse roots, and fine root tissues. We also report other properties of individuals (age, leaf size, leaf mass per area, wood density, nitrogen content of leaves and wood), as well as information about the growing environment (location, light, experimental treatment, vegetation type) where available. It is our hope that making these data available will improve our ability to understand plant growth, ecosystem dynamics, and carbon cycling in the world's vegetation.
ISSN: 0012-9658

hal-01535227
https://hal.archives-ouvertes.fr/hal-01535227
DOI : 10.1890/14-1889.1
PRODINRA : 306122