Éditeur(s) : HAL CCSD
Résumé : L'HNE et la Lf sont des protéines particulières car impliquées dans de nombreux processus physiologiques et pathologiques différents, connues comme des marqueurs de l'inflammation (inflammations pulmonaires et maladie de Crohn). Nous avons déterminé leur mécanisme d'action dans le cadre de la drépanocytose, une maladie génétique particulièrement polymorphe. Nous avons montré la présence de mutations inédites des gènes codant ces deux protéines dans le cas de la drépanocytose, mutations pouvant affecter le niveau d'expression et la structure de ces protéines. Des études sont en cours actuellement pour déterminer l'effet de ces mutations.
https://hal.archives-ouvertes.fr/hal-00201470

hal-00201470
https://hal.archives-ouvertes.fr/hal-00201470
https://hal.archives-ouvertes.fr/hal-00201470/document
https://hal.archives-ouvertes.fr/hal-00201470/file/PolyHL_Marianne_v1.pdf

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) : Edp Sciences S A
Résumé : Reared sea bass were submitted to six stressful situations: hyperoxia with or without hypercapnia, increased stocking density in an open flow or recirculating system, transfer to another tank and nodavirus injection. The potentially negative impact of these factors on the lives of sea bass was investigated by measuring 9 water parameters and 19 fish parameters including total serum protein (TSP). TSP has already been used to evaluate stress. The present study investigates data of previous and new experiments, concentrating on the potential use of TSP as a routine indicator to assess welfare in sea bass reared on fish farms. In the current experiment, oxygen and carbon dioxide were seen to affect levels of TSP, but alterations were too erratic to enable proper comparison, probably because they are normal components of the fish environment and become toxic only by dose increase. TSP decreased when stocking density increased. After transfer to another tank, TSP decreased to 14% for three weeks and then increased during the fourth week through compensative overproduction, before returning to normal levels after 2 months. The results confirmed that transfer is an important stress factor for fish, with cumulative effects for successive transfers. TSP alteration of nodavirus-injected fish depends on the type of symptoms, which can be divided into 3 groups: (i) dying fish, in which TSP increased sharply due to over-production of protein involved in non-specific defences and inflammation, then decreased dramatically before death; (ii) whirling fish, a group that included both fish that later died, in which TSP decreased, and fish that subsequently survived, in which TSP increased due to development of specific immunity; and (iii) asymptomatic fish, in which TPS was similar to control levels and which were probably insensitive to nodavirus and/or had developed defences. In this paper, different mechanisms of TSP alteration are proposed and the interest of TSP as a field parameter is discussed. TSP is a non-destructive parameter that is robust, easy to measure everywhere and cheap, representing a suitable way of monitoring the overall welfare of fish by its regular increase. It can be used only as a "warning" of poor rearing conditions, however, and further investigations would be needed to identify the specific stress or health disorder.
Aquatic Living Resources (0990-7440) (Edp Sciences S A), 2011-04 , Vol. 24 , N. 2 , P. 121-127

Droits : EDP Sciences, IFREMER, IRD 2011
http://archimer.ifremer.fr/doc/00043/15382/12740.pdf
DOI:10.1051/alr/2011130
http://archimer.ifremer.fr/doc/00043/15382/

Résumé : Les pathologies inflammatoires démyélinisantes primitives du système nerveux central (SNC) sont dominées par deux entités : la sclérose en plaques (SEP) et la neuromyélite optique (NMO). Ces deux pathologies se différencient par : 1. leur phénotype, la NMO se caractérisant par une myélite extensive dans le plan transversal et longitudinal et peu de lésions encéphaliques initiales ; 2. leur sévérité, le pronostic de la NMO étant moins bon que celui de la SEP ; 3. leur mécanisme immunologique, puisque l’immunité humorale domine nettement dans la NMO, cette pathologie répondant peu ou pas aux traitementshabituellement prescrits dans la SEP. Un anticorps sérique (IgG-NMO) a été retrouvé chez les patients atteints de NMO avec une sensibilité de 50-70% et une spécificité de 90-100%. Cet anticorps a pour cible le principal canal hydrique du SNC, l’aquaporine-4 (AQP4), qui se situe principalement sur les pieds astrocytaires jalonnant la barrière hémato-encéphalique. La SEP est relativement familière des neurologues car décrite sur le plan épidémiologique et dans son histoire naturelle depuis plus d’un siècle à travers de larges séries réalisées parfois en population générale. Son approche thérapeutique progresse suite à des essais contrôlés qui s’accumulent depuis maintenant près de 20 ans. Toutefois, la majorité des travaux ont été effectués chez les populations Caucasiennes en raison de sa plus grande fréquence dans ces populations. A l’inverse, la NMO garde encore un relatif mystère à cause de sa relative rareté, l’établissement très récent de critères diagnostiques et une physiopathologie très récemment éclaircie par la découverte de l’IgG-NMO qui a indiscutablement suscité un regain d’intérêt de cette affection. Ainsi, son incidence est quasiment inconnue de même que sa susceptibilité génétique. La progression du handicap de la NMO qu’il soit visuel ou moteur à l’évidence sévère, ne repose toujours pas sur des chiffres précis, la description des lésions neuroradiologiques reste encore très embryonnaire. Enfin, même s’il existe un consensus pour traiter énergiquement les poussées de NMO et les espacer, il n’existe quasiment aucune étude prospective.
Introduction: Aim of the study is to describe épidemiology, phenotype and treatment of demyelinating inflammatory diseases of the central nervous system (CNS) namely multiple sclerosis (MS) and neuromyelitis optica (NMO) in French West Indies.Epidemiology: MS emerged in the French West Indian (FWI) population with an incidence of 1.27/100 000 (CI 95%: 1.16-1.38) for the period 1992-2007 while incidence of NMO remained stable at 0.19/100,000 (CI 95%: 0.15–0.23). Both migration in Metropolitean France (MF) and decrease of sun exposure were risk factors for MS acquisition in FWI. Phenotype and treatment of NMO: NMO is a very rapidly disabling disease with median times to reach DSS 3, 6 and 8 of one year, 8 years and 22 years respectively. However, treatment by plasma exchanges were shown to reduce sequellae of NMO attacks ; mitoxantrone and rituximab reduced significantly annualized relapse rate (ARR) from 1.7 to 0.29 (p<10-4) and from 1,34 to 0,56 (p=0.0005) respectively, improving dramatically natural course of NMO.Phenotype and treatment of MS: Absence of Migration in MF in MS patients was found to be the strongest independent predictive factor of disability progression to DSS 6 (hazard ratio, 2.59; p=0.0002); beside short time to DSS3 (p=0.005), later age at onset (p=0.005), and multi-symptomatic onset (p=0.03). Treatment of MS by interferon beta-1 had a moderate impact in MS while natalizimab proved to be highly effective by reducing drastically ARR and inflammatory parameters on magnetic resonance imaging. Conclusion: Spectrum of demyelinating inflammatory disorders of CNS has reversed in French West Indies with overrepresentation of MS. Agressive therapy is needed to improve prognosis of NMO. Rapidly increasing of its incidence makes MS a new public health problem in French West Indies.

http://www.theses.fr/2012AGUY0511/document

Éditeur(s) : HAL CCSD Impact journals
Résumé : International audience
Interleukin (IL)-33 has been recently reported to be strongly pro-fibrogenic in various models of liver disease. Our aim was to study the role of endogenous IL-33 in a diet-induced model of steatohepatitis. IL-33 deficient mice and wild type (WT) littermates received a high-fat diet (HFD), or a standard diet for 12 weeks. The HFD-induced steatohepatitis was associated with an upregulation of IL-33 transcripts and protein. An insulin tolerance test revealed lower systemic insulin sensitivity in IL33-/-HFD mice than in WT-HFD mice. Nevertheless, IL-33 deficiency did not affect the severity of liver inflammation by histological and transcriptomic analyses, nor the quantity of liver fibrosis. Livers from HFD mice had more myeloid populations, markedly fewer NKT cells and higher proportion of ST2+ Treg cells and ST2+ type 2 innate lymphoid cells (ILC2), all unaffected by IL-33 deficiency. In conclusion, deficiency of endogenous IL-33 does not affect the evolution of experimental diet-induced steatohepatitis towards liver fibrosis.
ISSN: 1949-2553

hal-01578584
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578584
DOI : 10.18632/oncotarget.18335
PUBMED : 28611297

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1-2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases.
ISSN: 0041-008X

inserm-00813758
http://www.hal.inserm.fr/inserm-00813758
DOI : 10.1016/j.taap.2012.11.008
PUBMED : 23164666

Éditeur(s) : HAL CCSD Wiley Open Access
Résumé : 11 pages
International audience
The loss of regulating agents such as parasites is among the most important changes in biotic interactions experienced by populations established in newly colonized areas. Under a relaxed parasite pressure, individuals investing less in costly immune mechanisms might experience a selective advantage and become successful colonizers as they re-allocate resources to other fitness-related traits. Accordingly, a refinement of the evolution of increased competitive ability (EICA) hypothesis proposed that immunity of invasive populations has evolved toward a reduced investment in innate immunity, the most costly component of immunity, and an increased humoral immunity that is less costly. Biogeographical approaches comparing populations between native and expansion ranges are particularly relevant in exploring this issue, but remain very scarce. We conducted a biogeographical comparison between populations of Spectacled Thrush (Turdus nudigenis) from the native area (South America) and from the expansion range (Caribbean islands). First, we compared haemosporidian prevalence and circulating haptoglobin (an acute-phase protein produced during inflammation). Second, we challenged captive birds from both ranges with Escherichia coli lipopolysaccharides (LPS) and measured postchallenge haptoglobin production and body mass change. Birds from the expansion range showed lower haemosporidian prevalence and lower levels of haptoglobin than birds from the native range. In addition, the inflammation elicited by LPS injection and its associated cost in terms of body mass loss were lower in birds from the expansion range than in birds from the native range. In accordance with the enemy release hypothesis, our results suggest that range expansion is associated with a reduced infection risk. Our study also supports the hypothesis that individuals from newly established populations have evolved mechanisms to dampen the inflammatory response and are in accordance with one prediction of the refined EICA hypothesis, proposed to understand biological invasions.
ISSN: 2045-7758

hal-01403291
https://hal.archives-ouvertes.fr/hal-01403291
DOI : 10.1002/ece3.2486

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
Regarding nerves as simple cables and electrical conduits is a gross error that does not allow us to understand the anomalies and disorders observed postoperatively. Instead, nerves should be seen as a living tissue of which physiological regulation is as complex as that of the blood-brain barrier. This review describes the basic structure and functions of this blood-nerve barrier and highlights the mechanisms of its breakdown and the resultant disorders. For clinical practice, it is important to note that the diffusion of molecules from the perineurium or from the blood is very limited, and so the blood-nerve barrier is a major pharmacologic barrier. Any stress upon neural physiological balance, particularly the terminal vascular blood supply, will induce the classic inflammatory cascade. Due to the complexity of the vascular system, nerve ischaemia will occur more quickly when the terminal blood supply is compromised. This blood supply can adapt in a variety of ways but when these possibilities of adaptation are exceeded, tissue ischaemia may be more extensive. Also, even after the initial injury has subsided, inflammation can cause a secondary insult. This could be particularly important in some patients with subclinical neuropathy.
ISSN: 0265-0215

hal-01477207
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01477207
DOI : 10.1097/EJA.0000000000000590
PUBMED : 28146457

Éditeur(s) : HAL CCSD
Résumé : National audience
Aspirin (acetylsalicylic acid) has been used ever since the Antiquity for its painkilling and anti-inflammatory effects. Its antiplatelet properties have then extended its indications to the field of coronaropathy and vascular cerebral disease, and finally to vascular placental disease. Aspirin has been widely prescribed since the 1980's to prevent pre-eclampsia, intra-uterine growth retardation and fetal death of vascular origin. It has also been proposed to prevent unexplained recurrent miscarriages. Its use during pregnancy is considered as safe, provided the daily doses do not exceed 100mg. Aspirin has been proven efficient to prevent pre-eclampsia and fetal growth restriction in high-risk patients. The benefits of prescribing aspirin have been demonstrated neither for vascular placental disease prevention in low risk patients, nor in cases of unexplained recurrent miscarriages.
La Revue De Medecine Interne

hal-01659441
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01659441
DOI : 10.1016/j.revmed.2017.10.419
PUBMED : 29129461

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
The purpose of this investigation was to characterize the management and prognosis of severe Pneumocystis jirovecii pneumonia (PJP) in human immunodeficiency virus (HIV)-negative patients. An observational cohort study of HIV-negative adults with PJP documented by bronchoalveolar lavage (BAL) through Gomori-Grocott staining or immunofluorescence, admitted to one intensive care unit (ICU) for acute respiratory failure, was undertaken. From 1990 to 2010, 70 patients (24 females, 46 males) were included, with a mean age of 58.6 ± 18.3 years. The mean Simplified Acute Physiology Score (SAPS)-II was 36.9 ± 20.4. Underlying conditions included hematologic malignancies (n = 21), vasculitis (n = 13), and solid tumors (n = 13). Most patients were receiving systemic corticosteroids (n = 63) and cytotoxic drugs (n = 51). Not a single patient received trimethoprim-sulfamethoxazole as PJP prophylaxis. Endotracheal intubation (ETI) was required in 42 patients (60.0 %), including 38 with acute respiratory distress syndrome (ARDS). In-ICU mortality was 52.9 % overall, reaching 80.9 % and 86.8 %, respectively, for patients who required ETI and for patients with ARDS. In the univariate analysis, in-ICU mortality was associated with SAPS-II (p = 0.0131), ARDS (p < 0.0001), shock (p < 0.0001), and herpes simplex virus (HSV) or cytomegalovirus (CMV) on BAL (p = 0.0031). In the multivariate analysis, only ARDS was associated with in-ICU mortality (odds ratio [OR] 23.4 [4.5-121.9], p < 0.0001). PJP in non-HIV patients remains a serious disease with high in-hospital mortality. Pulmonary co-infection with HSV or CMV may contribute to fatal outcome.
ISSN: 0934-9723

inserm-00872789
http://www.hal.inserm.fr/inserm-00872789
DOI : 10.1007/s10096-012-1730-7
PUBMED : 22930407

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Apoptosis is a fundamental process that contributes to tissue homeostasis, immune responses, and development. The receptor CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance, and various lineages of malignant cells exhibit loss-of-function mutations in this pathway; therefore, CD95 was initially classified as a tumor suppressor gene. However, more recent data indicate that in different pathophysiological contexts, this receptor can transmit non-apoptotic signals, promote inflammation, and contribute to carcinogenesis. A comparison with the initial molecular events of the TNF-R signaling pathway leading to non-apoptotic, apoptotic, and necrotic pathways reveals that CD95 is probably using different molecular mechanisms to transmit its non-apoptotic signals (NF-κB, MAPK, and PI3K). As discussed in this review, the molecular process by which the receptor switches from an apoptotic function to an inflammatory role is unknown. More importantly, the biological functions of these signals remain elusive.
ISSN: 0006-3002

hal-01061290
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061290
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061290/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061290/file/BBAreviewsoncancer-legembre-final.pdf
DOI : 10.1016/j.bbcan.2014.04.007

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 Elsevier
Résumé : International audience
Co-exposure to environmental polycyclic aromatic hydrocarbons (PAHs) and interleukin (IL)-1β induces expression of the tumor-promoting cytokine IL-6 in cancer cells. The present study was designed to determine whether such an IL-6 up-regulation also occurs in response to co-treatment by PAHs and tumor necrosis factor (TNF)-α, an inflammatory cytokine commonly found in tumor microenvironment. Co-exposure to the prototypical PAH benzanthracene (BZA) and TNF-α was found to markedly induce mRNA expression and secretion of IL-6 in human breast cancer cells MCF-7, whereas exposure to either BZA or TNF-α alone was without significant effect. Co-treatment by BZA and TNF-α-containing conditioned media from human inflammatory macrophages similarly up-regulated IL-6 expression in MCF-7 cells. BZA/TNF-α-mediated IL-6 induction in MCF-7 cells was counteracted by silencing aryl hydrocarbon receptor (AhR), known to mediates most of PAH effects. IL-6 up-regulation was moreover associated with NF-κB activation and was abolished by using chemical NF-κB inhibitors or knocking-down expression of the p65/RelA NF-κB subunit. Taken together, these data indicate that co-exposure to BZA/TNF-α induces IL-6 expression by AhR- and NF-κB-dependent pathways in MCF-7 cancer cells. This regulation of IL-6 by environmental PAHs, that is dependent of inflammatory cytokine microenvironment, may contribute to the well-known carcinogenic properties of these organic pollutants.
ISSN: 0009-2797

inserm-00818896
http://www.hal.inserm.fr/inserm-00818896
DOI : 10.1016/j.cbi.2013.01.005
PUBMED : 23396138

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : National audience
Contexte La qualité de l’air ambiant dans les enceintes de transports ferroviaires souterrains (EFS) est caractérisée par des particules en suspension riches en métaux, majoritairement du fer, et en carbone, dont la concentration massique est très supérieure à celle mesurée dans l’air ambiant extérieur aux EFS. Cependant, les risques sanitaires chez les travailleurs des EFS liés aux polluants chimiques de l’air présents dans ces enceintes ferroviaires ont été peu étudiés. Dans ce contexte, l’Anses a été saisie afin de dresser un état des connaissances et réaliser une évaluation des risques sanitaires (ERS) chez les travailleurs des EFS. Méthodes Un groupe de travail pluridisciplinaire a analysé les études publiées jusqu’en décembre 2014 et des données communiquées par les exploitants de transport. L’ERS a porté sur les travailleurs de l’exploitation, l’organisation du transport et des services, et des commerces qui exercent une activité durant les horaires de trafic des rames de voyageurs. L’exposition chronique des travailleurs a été estimée à partir des données de concentration inhalée en particules (PM2,5 et PM10), en éléments métalliques, en carbone, en hydrocarbures aromatiques polycycliques particulaires et en hydrocarbures aromatiques monocycliques, issues d’une campagne transversale de métrologie individuelle de la RATP. Cette exposition estimée a ensuite été comparée à une valeur toxicologique de référence (VTR ajustée, VLEP, NOAECHEC) pour calculer un indicateur de risque. Résultats Les risques sanitaires en lien avec les éléments métalliques évalués individuellement semblent négligeables. Concernant l’exposition chronique aux particules, une inflammation des voies respiratoires et des effets consécutifs à cette inflammation sont probables, sur la base d’un effet démontré par une étude de toxicité aiguë chez l’animal. Par analogie avec les particules de l’air ambiant extérieur, des effets délétères sont attendus sur la santé cardiovasculaire et respiratoire en lien avec l’exposition chronique de ces travailleurs aux particules des EFS. L’ERS présente néanmoins des incertitudes notables compte tenu notamment du corpus d’études épidémiologiques assez peu informatif et de l’absence d’étude toxicologique d’exposition chronique. Conclusion Des effets sanitaires sont attendus en relation avec l’exposition chronique des travailleurs à la pollution de l’air des EFS. Des travaux sont recommandés pour combler les lacunes des connaissances sur la toxicité à long terme des particules de l’air de ces enceintes ferroviaires, mais également sur l’exposition de certaines catégories de travailleurs de la maintenance vraisemblablement plus exposés
ISSN: 1775-8785

hal-01331986
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01331986
DOI : 10.1016/j.admp.2016.03.448
PUBMED : 26334607

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 Elsevier [Commercial Publisher]
Résumé : International audience
BACKGROUND: Pneumocystis jiroveci pneumonia in HIV-negative immunocompromised patients is associated with high mortality rates. Although trimethoprim-sulfamethoxazole (TMP-SMX) provides a very effective prophylaxis, pneumocystosis still occurs and may even be emerging, due to sub-optimal characterization of patients most at risk, hence precluding targeted prophylaxis. METHODS: We retrospectively analyzed all cases of documented pneumocystosis in HIV-negative patients admitted in our institution, a referral center in the area, from January 1990 to June 2010, and extracted data on their underlying condition(s). To estimate incidence rates within each condition, we estimated the number of patients followed-up in our area for each condition, by measuring the number of patients admitted with the corresponding international classification diagnostic code, through the national hospital discharge database (PMSI). RESULTS: From 1990 to 2010, 293 cases of pneumocystosis were documented, of whom 154 (52.6%) tested negative for HIV. The main underlying conditions were hematological malignancies (32.5%), solid tumors (18.2%), inflammatory diseases (14.9%), solid organ transplant (12.3%), and vasculitis (9.7%). Estimated incidence rates could be ranked in three categories: i) high risk (incidence rates extgreater 45 cases per 100,000 patient-year): polyarteritis nodosa, granulomatosis with polyangiitis, polymyositis/dermatopolymyositis, acute leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma; ii) intermediate risk (25-45 cases per 100,000 patient-year): Waldenström macroglobulinemia, multiple myeloma, and central nervous system cancer; and iii) low risk ( extless 25 cases per 100,000 patient-year): other solid tumors, inflammatory diseases, and Hodgkin lymphoma. CONCLUSIONS: These estimates may be used as a guide to better target pneumocystosis prophylaxis in the groups most at risk.
ISSN: 0002-9343

hal-01063911
https://hal.archives-ouvertes.fr/hal-01063911
https://hal.archives-ouvertes.fr/hal-01063911/document
https://hal.archives-ouvertes.fr/hal-01063911/file/1-s2.0-S0002934314005907-main.pdf
DOI : 10.1016/j.amjmed.2014.07.010

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Bronchoalveolar lavage (BAL) is a major diagnostic tool in lung diseases, including viral respiratory infections. We aimed to better define the situations where viral tests should be performed on BAL fluid (BALF). We retrospectively studied all cases where viral tests [immunofluorescence, immunocytochemistry, viral culture, and/or polymerase chain reaction (PCR)] were performed on BALF during a period of 1 year (2008) in our institution. We compared the characteristics of patients with virus-positive versus virus-negative BALF. Of the 636 BALF samples sent to the microbiology laboratory, 232 underwent viral tests. Of these, 70 (30 %) were positive and identified 85 viruses: herpes simplex virus (HSV)-1 (n = 27), cytomegalovirus (CMV, n = 23), Epstein-Barr virus (EBV, n = 18), human herpesvirus (HHV)-6 (n = 12), respiratory syncytial virus (RSV, n = 3), rhinovirus (n = 1), and adenovirus (n = 1). The variables associated with positive viral tests on univariate analysis were immunosuppression [human immunodeficiency virus (HIV), corticosteroids >10 mg/day for ≥3 weeks, or other immunosuppressive therapy], ground-glass attenuations on computed tomography (CT) scanning, late-onset ventilator-associated pneumonia (VAP), and durations of (i) hospital stay, (ii) intensive care unit (ICU) stay, and (iii) mechanical ventilation before BAL (p < 0.01 for each comparison). On multivariate analysis, only immunosuppression [odds ratio (OR) 6.4, 95 % confidence interval (CI) [2.8-14.3], p < 0.0001] and ground-glass attenuations (OR 3.7, 95 % CI [1.8-7.7], p = 0.0004) remained associated with virus-positive BAL. None of the viral tests performed on BALF for the initial assessment of diffuse infiltrative lung disease (n = 15) was positive. PCR improved the diagnostic yield of viral tests on BALF by 50 %. Testing for viruses on BALF should be mostly restricted to immunocompromised patients with acute respiratory diseases and/or patients with unexplained ground-glass attenuations on CT scanning.
ISSN: 0934-9723

hal-00873158
https://hal.archives-ouvertes.fr/hal-00873158
DOI : 10.1007/s10096-012-1791-7
PUBMED : 23238685

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 Physiological Society
Résumé : International audience
Excessive or persistent inflammation and hepatocyte death are the key triggers of liver diseases. The poly(ADP-ribose) polymerase (PARP) proteins induce cell death and inflammation. Chemical inhibition of PARP activity protects against liver injury during concanavalin A (ConA)-induced hepatitis. In this mice model, ConA activates immune cells, which promote inflammation and induce hepatocyte death, mediated by the activated invariant natural killer T (iNKT) lymphocyte population. We analyzed immune cell populations in the liver and several lymphoid organs, such as the spleen, thymus, and bone marrow in Parp2-deficient mice to better define the role of PARP proteins in liver immunity and inflammation at steady state and during ConA-induced hepatitis. We show that 1) the genetic inactivation of Parp2, but not Parp1, protected mice from ConA hepatitis without deregulating cytokine expression and leucocyte recruitment; 2) cellularity was lower in the thymus, but not in spleen, liver, or bone marrow of Parp2-/- mice; 3) spleen and liver iNKT lymphocytes, as well as thymic T and NKT lymphocytes were reduced in Parp2 knockout mice. In conclusion, our results suggest that the defect of T-lymphocyte maturation in Parp2 knockout mice leads to a systemic reduction of iNKT cells, reducing hepatocyte death during ConA-mediated liver damage, thus protecting the mice from hepatitis.NEW & NOTEWORTHY The genetic inactivation of Parp2, but not Parp1, protects mice from concanavalin A hepatitis. Immune cell populations are lower in the thymus, but not in the spleen, liver, or bone marrow of Parp2-deficient mice compared with wild-type mice. Spleen and liver invariant natural killer T (NKT) lymphocytes, as well as thymic T and NKT lymphocytes, are reduced in Parp2-deficient mice
ISSN: 0193-1857

hal-01630440
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01630440
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01630440/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01630440/file/102513_1_merged_1499199857-1.pdf
DOI : 10.1152/ajpgi.00436.2016

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