Résumé : Les deux principaux objectifs de ce travail sont de proposer des outils pour la selection d'animaux résistants aux strongles gastro-intestinaux, parasites du tube digestif, et de faire progresser la compréhension des mécanismes de résistance chez la chèvre créole. La variabilité génétique du caractère de résistance au parasitisme digestif a été étudiée afin de vérifier quels critères décrivant le mieux la résistance, peuvent être utilisés pour la sélection. L'ensemble des résultats obtenus suggèrent que le critère d'excrétion d'oeufs et le critère d'éosinophilie sont les plus adaptés pour un schéma de sélection puisqu'ils possèdent une héritabillté moyenne et représentent le mieux la résistance. De plus, ils ne semblent pas en opposition avec le poids, principal critère de production. Le déterminisme génétique de la résistance aux strongles gastro-intestinaux a été étudié et a permis de mettre en évidence l'existence d'un gène majeur pour la résistance chez la population de chèvre créole. De plus, la primo-détection de qtl a permis d'identifier 13 régions du génome ayant un effet sur les critères de résistance. Les mécanismes responsables de la résistance aux strongles gastro-intestinaux ont également été à l'étude. L'ensemble des résultats met en évidence le rôle des éosinophiles dans la mise en place de la résistance aux strongles gastro-intestinaux. L'activité des immunogobulines e semblent dirigés vers les larves l3 d'haemonchus contortus et suggère la mise en place d'une réaction protectrice. Chez la chèvre créole. Ces deux mécanismes semblent donc jouer un rôle important dans la mise en place de la résistance aux strongles gastro-intestinaux
The two main objectives of this work are to propose tools for the selection of resistant animals to gastrointestinal nematodes and advance knowledge on mechanisms of resistance of creole goats. this work has analysed the genetic variability of resistance to digestive parasitism in order to determine which criteria best describes the resistance and can be use for selection. the overall results suggest that the egg excretion and the eosinophilia are the criteria most suitable for a breeding scheme because they have moderate heritability estimates and best represent the resistance. moreover, they do not seem in conflict with the weight, the main criterion of production. the genetic determinism of resistance to gastrointestinal parasites has been studied and has highlighted the existence of a major gene for resistance in creole goats. in addition, the primodetection of qtl identified 13 genomic regions that affect the resistance. the mechanisms behind the resistance to gastrointestinal parasites were also studied and first hypothesis regarding the involvment of the immune response in resistance have been made in goats. the overall results highlighted the role of eosinophils in the development of resistance to gastrointestinal nematodes. the activity of immunoglobulin e seems directed toward l3 larvae of haemonchus contortus and may be imply in the establishment of a protective response agasint nematode parasites. in creole goats, these two mechanisms seem to play an important role in the development of resistance to gastrointestinal nematode infections

http://www.theses.fr/2011AGUY0407/document

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The underlying cause of morbidity in cystic fibrosis (CF) is the decline in lung function, which results in part from chronic inflammation. Inflammation and infection occur early in infancy in CF and the role of innate immune defense in CF has been highlighted in the last years. Once thought simply to be consumers of bacteria, macrophages have emerged as highly sensitive immune cells that are located at the balance point between inflammation and resolution of this inflammation in CF pathophysiology. In order to assess the potential role of macrophage in CF, we review the evidence that: (1) CF macrophage has a dysregulated inflammatory phenotype; (2) CF macrophage presents altered phagocytosis capacity and bacterial killing; and (3) lipid disorders in CF macrophage affect its function. These alterations of macrophage weaken innate defense of CF patients and may be involved in CF disease progression and lung damage.
ISSN: 1569-1993

hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/file/Chouly-The%20impact%20of%20impaired%20macrophage%20functions.pdf
DOI : 10.1016/j.jcf.2016.10.011

Résumé : By looking at the common thread between 4 programs* in which the IFREMER Palavas (34, Languedoc-Roussillon region in France) station took part, this report show the evolution over 20 years in the perception of the pathology of farmed fish, and of the sea bass in particular (Dicentrarchus labrax). During the 1990’s farming techniques became sufficiently reliable to enable to distinguish between problems of a zootechnical nature and those with a pathological origin. In anticipation of future illnesses, the necessary tools and monitoring were implemented in order to study the immune system of the sea bass. These methods arose from the recent creation of anti-immunoglobin monoclonal probes in the sea bass. These techniques, together with others, served to search for a solution to the nodavirus epidemic which struck in1996. In the absence of a cure for this virus, the research focused on knowledge of the virus, its epidemiology and vaccine development. Despite interesting scientific results, the solution withheld to curb the Nodavirus epidemic was zootechnical. This pragmatic outcome catalysed reflections on the role of pathology, leading to notions of health, animal well-being and image. Management choices in the health of farmed fish stocks became a parameter, amongst others, included in a global commercial and farming policy. * Définition des critères d’évaluation de l’immunocompétente chez le loup et le turbot. UMR1 Université Montpellier II IFREMER ; Nodavirus disease of cultured marine fish in Europe. FAIR PL98 4036 EU; Recherche de moyens de dépistage et prévention de la nodavirose du bar. ANVAR 9804041J ; Welfare and Health in Sustainable Aquaculture WEALTH. E.U N°501984.
En prenant comme fil conducteur les travaux de 4 programmes* auxquels a participé la station IFREMER de Palavas (34), ce rapport montre l’évolution sur 20 ans de la perception de la pathologie des poissons d’élevages et du loup en particulier (Dicentrarchus labrax). Dans les années 1990 les techniques d’élevages devinrent suffisamment fiables pour permettre de distinguer les problèmes d’origines zootechniques de ceux d’origines pathologiques. En prévision des futures maladies potentielles, les outils d’étude et de suivi du système immunitaire spécifique du loup furent mis en place. Ils découlaient de la création récente de sondes monoclonales anti-immunoglobulines de loup. Ces techniques, couplées à d’autres, servirent à chercher une solution à l’épidémie de nodavirose des années 1996. En l’absence de traitement pour un virus l’accent fut mis sur la connaissance du virus, de son épidémiologie et de la vaccination. Bien que les résultats scientifiques furent très satisfaisants la solution trouvée pour juguler l’épidémie de Nodavirose fut zootechnique. Cette issue pragmatique catalysa une réflexion sur le rôle de la pathologie qui maturait depuis plusieurs années et qui déboucha sur la notion de santé, de bien être des animaux et d’image. Les choix de gestion de la santé des cheptels devinrent un paramètre, parmi d’autres, s’incluant dans d’une politique globale d’élevage et commerciale * Définition des critères d’évaluation de l’immunocompétente chez le loup et le turbot. UMR1 Université Montpellier II IFREMER ; Nodavirus disease of cultured marine fish in Europe. FAIR PL98 4036 EU; Recherche de moyens de dépistage et prévention de la nodavirose du bar. ANVAR 9804041J ; Welfare and Health in Sustainable Aquaculture WEALTH. E.U N°501984.

Droits : 2013 Ifremer
http://archimer.ifremer.fr/doc/00167/27866/26103.pdf
http://archimer.ifremer.fr/doc/00167/27866/26105.pdf
http://archimer.ifremer.fr/doc/00167/27866/26106.pdf
http://archimer.ifremer.fr/doc/00167/27866/

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Macrophages (MΦ), well-known to play an important role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP). Potential effects of DEPs towards MΦ polarization, a key hall-mark of MΦ physiology, remain however poorly documented. This study was therefore designed to evaluate the effects of a reference DEP extract (DEPe) on human MΦ polarization. Human blood monocytes-derived MΦ were incubated with IFNγ+LPS or IL-4 to obtain M1 and M2 subtypes, respectively; a 24 h exposure of polarizing MΦ to 10 μg/ml DEPe was found to impair expression of some macrophagic M1 and M2 markers, without however overall inhibition of M1 and M2 polarization processes. Notably, DEPe treatment increased the secretion of the M1 marker IL-8 and the M2 marker IL-10 in both MΦ subtypes, whereas it reduced lipopolysaccharide-induced IL-6 and IL-12p40 secretion in M1 MΦ. In M2 MΦ, DEPe exposure led to a reduction of CD200R expression and of CCL17, CCL18 and CCL22 secretion, associated with a lower chemotaxis of CCR4-positive cells. DEPe activated the Nrf2 and AhR pathways and induced expression of their reference target genes such as Hmox-1 and cytochrome P-4501B1 in M1 and M2 MΦ. Nrf2 or AhR silencing through RNA interference prevented DEPe-related down-regulation of IL-6. AhR silencing also inhibited the down-secretion of IL-12p40 and CCL18 in M1- and M2-DEPe-exposed MΦ, respectively. DEPs are therefore likely to alter expression of some M1 and M2 markers in an AhR- and Nrf2-dependent manner; such regulations may contribute to deleterious immune effects of atmospheric DEP.
ISSN: 1932-6203

hal-01122723
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122723
PUBMED : 25710172
DOI : 10.1371/journal.pone.0116560

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The susceptibility of Anopheles mosquitoes to Plasmodium infections relies on complex interactions between the insect vector and the malaria parasite. A number of studies have shown that the mosquito innate immune responses play an important role in controlling the malaria infection and that the strength of parasite clearance is under genetic control, but little is known about the influence of environmental factors on the transmission success. We present here evidence that the composition of the vector gut microbiota is one of the major components that determine the outcome of mosquito infections. A. gambiae mosquitoes collected in natural breeding sites from Cameroon were experimentally challenged with a wild P. falciparum isolate, and their gut bacterial content was submitted for pyrosequencing analysis. The meta-taxogenomic approach revealed a broader richness of the midgut bacterial flora than previously described. Unexpectedly, the majority of bacterial species were found in only a small proportion of mosquitoes, and only 20 genera were shared by 80% of individuals. We show that observed differences in gut bacterial flora of adult mosquitoes is a result of breeding in distinct sites, suggesting that the native aquatic source where larvae were grown determines the composition of the midgut microbiota. Importantly, the abundance of Enterobacteriaceae in the mosquito midgut correlates significantly with the Plasmodium infection status. This striking relationship highlights the role of natural gut environment in parasite transmission. Deciphering microbe-pathogen interactions offers new perspectives to control disease transmission.
ISSN: 1553-7366

hal-01546176
https://hal.archives-ouvertes.fr/hal-01546176
DOI : 10.1371/journal.ppat.1002742

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/

Éditeur(s) : HAL CCSD Hindawi Publishing Corporation
Résumé : International audience
HLA-G is a nonclassical major histocompatibility complex molecule first described at the maternal-fetal interface, on extravillous cytotrophoblasts. Its expression is restricted to some tissues in normal conditions but increases strongly in pathological conditions. The expression of this molecule has been studied in detail in cancers and is now also beginning to be described in infectious diseases. The relevance of studies on HLA-G expression lies in the well known inhibitory effect of this molecule on all cell types involved in innate and adaptive immunity, favoring escape from immune control. In this review, we summarize the features of HLA-G expression by type of infections (i.e, bacterial, viral, or parasitic) detailing the state of knowledge for each pathogenic agent. The polymorphism, the interference of viral proteins with HLA-G intracellular trafficking, and various cytokines have been described to modulate HLA-G expression during infections. We also discuss the cellular source of HLA-G, according to the type of infection and the potential role of HLA-G. New therapeutic approaches based on synthetic HLA-G-derived proteins or antibodies are emerging in mouse models of cancer or transplantation, and these new therapeutic tools may eventually prove useful for the treatment of infectious diseases.
ISSN: 2314-8861

hal-01063925
https://hal.archives-ouvertes.fr/hal-01063925
https://hal.archives-ouvertes.fr/hal-01063925/document
https://hal.archives-ouvertes.fr/hal-01063925/file/Immunomodulatory%20Properties%20of%20HLA-G.pdf
DOI : 10.1155/2014/298569

Résumé : Les bactéries appartenant au genre Vibrio sont largement répandues en milieu côtier tropical et tempéré. Certaines espèces sont pathogènes pour l'homme, comme Vibrio cholerae 01 et 0139 responsables du choléra, ou V. cholerae non-01/non-0139, V. parahaemolyticus et V. vulnificus impliqués dans de nombreuses pathologies (gastro-entérites, des septicémies et autres infections). En France, le risque associé à la présence de vibrions en milieu marin est mal évalué. Ce rapport fait le bilan des données disponibles sur la contamination littorale et les infections à vibrions en France. Une large place a été consacrée aux études écologiques, réalisées sur les sites d'implantation des centrales nucléaires sur le littoral français. Dans la population, le nombre d'infections est restreint car seules les pathologies graves sont recensées. Il s'agit de cas isolés, le plus souvent immuno-déprimés, enregistrés en été et en automne. Le milieu marin (par contact, baignade ou consommation de produits de la mer) est très souvent cité comme source probable de la contamination. Un petit nombre d'espèces de vibrions est concerné (V. alginolyticus, V. vulnificus, V. parahaemolyticus, V. cholerae non-01/non-0139 et V. hollisae). Dans l'environnement marin, l'espèce dominante est V. alginolyticus ; V. vulnificus et V. parahaemolyticus sont détectés sporadiquement. Le suivi, pendant plus de dix ans, des effets d'un réchauffement artificiel des eaux littorales à Gravelines a souligné des modifications sur les populations de Vibrio marins (présence des Vibrio en hiver, augmentation de la densité bactérienne et de la diversité spécifique). Le développement de techniques de biologie moléculaire devrait permettre une meilleure évaluation du risque sanitaire en quantifiant et en caractérisant les vibrions présents en milieu côtier (stade viable non cultivable, maintien du pouvoir pathogène et virulence des souches présentes).

Droits : info:eu-repo/semantics/openAccess
http://archimer.ifremer.fr/doc/00104/21545/19124.pdf
DOI:Ifremer 2002
http://archimer.ifremer.fr/doc/00104/21545/

Résumé : The New-Caledonian shrimp industry is based on the controlled reproduction of the shrimp Litopenaeus stylirostris, a species which was introduced in the 80s. The major difficulty to which the industry has been faced for 10 years is the occurrence of the "syndrome 93", which corresponds to mortality phases when the temperature falls down in April-May-June. This mortality is associated to the pathogenic bacteria Vibrio penaecida and is expressed at different levels which are variable from year ta year and from pond to pond. No resistance to this pathology has been developed spontaneously. This is likely due to the protocole used to rear spawners, which does not allow to implement an efficient selective pressure at each generation An experimental selection on the criteria of survival after picks of syndrome 93 has been conducted at the Laboratoire Aquacole de Calédonie. The 3rd selected generation demonstrates survival rates improved by 20% during experimental infections with V. penaeicida in comparison with a non selected control population of same genetic origin. The comparison of the correlated responses on the level of expression of 5 genes which are potentially implicated in immunity phenomena (Peneidins, lysozyme, transglutaminase. profiline, annexine) shows that the selected population has a level of expression in lyzozyme twice higher than the control population. This result suggests that the lysozyme could be a genetic marker which could be used in a selective breeding program to he developed in relation with the private hatcheries.
La filière crevette de Nouvelle-Calédonie repose sur la maîtrise de la reproduction contrôlée de la crevette Litopenaeus stylirostris, espèce introduite dans les années 80. La difficulté majeure que rencontre la filière depuis une dizaine d'années est la récurrence du « syndrome 93 », qui correspond à des épisodes de mortalités lors des baisses de température en avril-mai-juin. Ces mortalités sont associées à la bactérie pathogène Vibrio penaeicida et s'expriment à des niveaux d'intensité variable d'une année à l'autre et d'un bassin à l'autre. Aucune résistance vis-à-vis de cette pathologie ne s'est développée spontanément. Ceci est vraisemblablement lié au protocole employé pour l'élevage des géniteurs qui ne permet pas d'exercer une pression de sélection efficace à chaque génération. Une expérience de sélection sur un critère de survie à des épisodes de syndrome 93 a été menée au Laboratoire Aquacole de Calédonie. La 3ème génération sélectionnée montre des survies améliorées de l'ordre de 20% lors d'infections expérimentales à V. penaeicida par rapport à une population témoin non sélectionnée de même origine génétique. La comparaison des réponses corrélées sur le niveau d'expression de 5 gènes potentiellement impliqués dans les phénomènes de défense immunitaire (penaeidine, lysozyme, transglutaminase, profiline, annexine) montre que la population sélectionnée a un niveau d'expression en lysozyme deux fois plus élevé que la population témoin. Ce résultat suggère que le lysozyme pourrait être un marqueur génétique utilisable dans un programme de sélection à développer en relation avec les écloseries de production.

Droits : 2003 Ifremer
http://archimer.ifremer.fr/doc/00109/22020/19643.pdf
http://archimer.ifremer.fr/doc/00109/22020/

Éditeur(s) : HAL CCSD
Résumé : Inorganic arsenic is an environmental human carcinogen, but is also studied these days because of its potential effectiveness in curing chronic inflammatory disease. Indeed, this metalloid possesses immunosuppressive properties which can dysregulate physiological mechanisms involved in immune defense, or reduce inflammation associated with those inflammatory diseases. Inorganic arsenic is known mainly to alter functions of T cells and macrophages. However, it is unknown whether arsenic targets dendritic cells (DCs). Yet, this antigen presenting cells plays a major role in the immunosurveillance, and is involved in the physiopathology of chronic inflammatory diseases. So, the aim of my thesis work was to study the effects of inorganic arsenic on in vitro differenciation and maturation of dendritic cells from human monocytes. Our results mainly shows that concentrations corresponding to those measured in environmentally exposed people, inhibits DCs secretion of proinflammatory cytokines, which plays a major role in activation and polarization of T cells. Particularly, arsenic strongly impairs expression and secretion of interleukine 12 (IL-12) by an underlying molecular mechanism involving Nrf2. Finally, this work shows that inorganic arsenic has immunosuppressive properties on the physiology in vitro of human dendritic cells. Immunotoxicity may then contribute to the metalloid toxicity in environmentally exposed people. This element could be taken into account when determining arsenic effects in curing some chronic inflammatory diseases.
L’arsenic inorganique est un contaminant environnemental, cancérogène pour l’homme, mais également un métalloïde étudié, aujourd’hui, dans le traitement de maladies inflammatoires chroniques. Il possède des propriétés immunosuppressives pouvant déréguler les mécanismes physiologiques de défense ou bloquer l’exacerbation de réponses inflammatoires chroniques. L’arsenic inorganique altère principalement les fonctions des lymphocytes T et des macrophages. En revanche, l’impact du métalloïde sur la physiologie des cellules dendritiques (DCs) est peu connu. Pourtant, ces cellules présentatrices d’antigène jouent un rôle fondamental dans les processus d’immunosurveillance et sont très impliquées dans la physiopathologie des maladies inflammatoires chroniques. Dans ce contexte, les objectifs de mon travail de thèse étaient d’étudier les effets de l’arsenic inorganique sur la différenciation et la maturation in vitro de DCs générées à partir de monocytes humains. Nos résultats démontrent principalement que des concentrations de métalloïde, compatibles avec les taux plasmatiques d’arsenic mesurés chez les individus exposés, répriment la capacité des DCs à sécréter différentes cytokines pro-inflammatoires jouant un rôle essentiel dans l’activation et la polarisation des lymphocytes T. En particulier, l’arsenic inhibe l’expression et la sécrétion de l’interleukine-12 par un mécanisme moléculaire impliquant le facteur de transcription Nrf2. Au total, ces travaux de thèse démontrent que l’arsenic inorganique possède des propriétés immunosuppressives sur la physiologie in vitro des DCs humaines. Cette immunotoxicité pourrait contribuer à la toxicité du métalloïde chez l’homme exposé par voie environnementale, et être prise en compte pour déterminer les effets de l’arsenic dans le traitement de certaines maladies inflammatoires chroniques
https://tel.archives-ouvertes.fr/tel-01135887

NNT : 2013REN1B013
tel-01135887
https://tel.archives-ouvertes.fr/tel-01135887
https://tel.archives-ouvertes.fr/tel-01135887/document
https://tel.archives-ouvertes.fr/tel-01135887/file/pdf2star-1392896105-Th--se-M--linda-Macoch2.pdf

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Interleukin-33 (IL-33), a cytokine belonging to the IL-1 family, is crucially involved in inflammatory pathologies including liver injury and linked to various modes of cell death. However, a link between IL-33 and necroptosis or programmed necrosis in liver pathology remains elusive. We aimed to investigate the regulation of IL-33 during necroptosis-associated liver injury. The possible regulation of IL-33 during liver injury by receptor-interacting protein kinase 1 (RIPK1) and poly(ADP-ribose) polymerase 1 (PARP-1) was investigated in mice in vivo and in hepatic stellate cells in vitro. The liver immunohistopathology, flow cytometry, serum transaminase measurement, ELISA, and qPCR-based cytokine measurement were carried out. By using a chemical approach, we showed that pretreatment of mice with Necrostatin-1 (Nec-1) (inhibitor of RIPK1) and/or PJ34 (inhibitor of PARP-1) significantly protected mice against concanavalin A (ConA) liver injury (aspartate amino-transferase (AST)/alanine amino-transferase (ALT)) associated with down-regulated hepatocyte-specific IL-33 expression. In contrast, the expression level of most systemic cytokines (except for IL-6) or activation of liver immune cells was not altered by chemical inhibitors rather an increased infiltration of neutrophils in the liver. During polyinosine-polycytidylic acid (Poly(I:C))-induced acute hepatitis, liver injury and hepatocyte-specific IL-33 expression was also inhibited by PJ34 without any protective effect of PJ34 in CCl4-induced liver injury. Moreover, PJ34 down-regulated the protein expression of IL-33 in activated hepatic stellate cells by cocktail of cytokines or staurosporine in vitro. In conclusion, we evidenced that the Nec-1/PJ34 is a potent inhibitor of liver injury and Nec-1/PJ34 down-regulated hepatocyte-specific IL-33 expression in the liver in vivo or in hepatic stellate cells in vitro, suggesting IL-33 as a possible readout of necroptosis-involved liver pathologies. Necroptosis inhibitors can protect mice against liver injury induced by ConA or Poly(I:C). IL-33 expression in liver injury in vivo is inhibited by PJ34. IL-33 expression in hepatic stellate cells in vitro is inhibited by PJ34. Hepatocyte-specific IL-33 expression is down-regulated by Nec-1/PJ34 during hepatitis. IL-33 is a new marker of necroptosis-associated liver injuries.
ISSN: 0946-2716

hal-01134319
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134319
DOI : 10.1007/s00109-015-1270-6
PUBMED : 25747661

Éditeur(s) : HAL CCSD Cambridge University Press (CUP)
Résumé : International audience
Leishmania parasites can escape the immune response by invading cell types lacking leishmanicidal mechanisms. Silent persistence of Leishmania parasites in the host organism is responsible for asymptomatic carriage and relapses after cured leishmaniasis. Here, we studied the interaction between Hepatic Stellate Cells (HSC) and Leishmania. An original model of human HSC in primary culture infected with L. donovani was developed. The presence of intracellular parasites was studied and quantified using optical and confocal microscopy. HSC characteristics were studied using microscopy, methylene blue assay, long-term cultures and qPCR. We showed for the first time that human HSC are permissive to L. donovani infection, with no modification of HSC survival, growth rate and proinflammatory and fibrogenic characteristics. Intracellular parasites did not replicate but HSC had no effect on their survival. Indeed, after a 40-day culture, infected HSC cultures transferred on NNN medium yielded new promastigotes that were able to proliferate and efficiently infect new cells. HSC are permissive to L. donovani, with neither parasite killing nor apparent cell damage. Thus, HSC could act as potent sanctuary cells for Leishmania in the liver, which could partially explain parasite reactivation after an asymptomatic carriage or a cured visceral leishmaniasis.
ISSN: 0031-1820

inserm-00825803
http://www.hal.inserm.fr/inserm-00825803
DOI : 10.1017/S0031182012001965
PUBMED : 23253952

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 Elsevier
Résumé : International audience
The transcription factor nuclear factor-erythroid 2-related-2 (Nrf2) controls cellular redox homeostasis and displays immunomodulatory properties. Nrf2 alters cytokine expression in murine T cells, but its effects in human T lymphocytes are unknown. This study investigated the expression and activity of Nrf2 in human activated CD4(+) T helper lymphocytes (Th cells) that mediate the adaptive immune response. Th cells were isolated from peripheral blood mononuclear cells and activated with antibodies against CD3 and CD28, mimicking physiologic Th cell stimulation by dendritic cells. Nrf2 is hardly detectable in unstimulated Th cells. Activation of Th cells rapidly and strongly increases the levels of Nrf2 protein by increasing NRF2 gene transcription. Th cell activation also enhances mRNA and protein levels of Nrf2 target genes encoding antioxidant enzymes. Blocking Nrf2 expression using chemical inhibitors or siRNAs prevents these gene inductions. Pretreatment with inorganic arsenic, a Nrf2 inducer that does not alter NRF2 gene expression, increases protein level and transcriptional activity of Nrf2 induced by Th cell stimulation. Inorganic arsenic enhances nuclear translocation of Nrf2, its interaction with the coactivator protein p300, and its DNA binding activity. Inhibition of Nrf2 expression abrogates the effects of inorganic arsenic on mRNA levels of antioxidant genes, but does not alter the expression of IL-2, TNF-α, interferon-γ, or IL-17 in Th cells activated in the absence or presence of the metalloid. In conclusion, this study demonstrates for the first time that stimulation of human Th cells increases transcription of the NRF2 gene and activity of the Nrf2 protein. However, modulation of Nrf2 levels does not modify the secretion of inflammatory cytokines from these T lymphocytes.
ISSN: 0891-5849

hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/file/Nrf2_expression_and_activity_in_human_T_lymphocytes_accepted.pdf
DOI : 10.1016/j.freeradbiomed.2014.03.006

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Lung diseases are aggravated by exposure to diesel exhaust particles (DEPs) found in air pollution. Macrophages are thought to play a crucial role in lung immune response to these pollutants, even if the mechanisms involved remain incompletely characterized. In the present study, we demonstrated that classically and alternative human macrophages (MΦ) exhibited increased secretion of PDGF-B in response to DEP extract (DEPe). This occurred via aryl hydrocarbon receptor (AhR)-activation because DEPe-induced PDGF-B overexpression was abrogated after AhR expression knock-down by RNA interference, in both M1 and M2 polarizing MΦ. In addition, TCDD and benzo(a)pyrene, two potent AhR ligands, also significantly increased mRNA expression of PDGF-B in M1 MΦ, whereas some weak ligands of AhR did not. We next evaluated the impact of conditioned media (CM) from MΦ culture exposed to DEPe or of recombinant PDGF-B onto lung fibroblast proliferation. The tyrosine kinase inhibitor, AG1295, prevents phosphorylations of PDGF-Rβ, AKT and ERK1/2 and the proliferation of MRC5 fibroblasts induced by recombinant PDGF-B and by CM from M1 polarizing MΦ, strongly suggesting that the PDGF-BB secreted by DEPe-exposed MΦ is sufficient to activate the PDGF-Rβ pathway of human lung fibroblasts. In conclusion, we demonstrated that human MΦ, whatever their polarization status, secrete PDGF-B in response to DEPe and that PDGF-B is a target gene of AhR. Therefore, induction of PDGF-B by DEP may participate in the deleterious effects towards human health triggered by such environmental urban contaminants.
ISSN: 0041-008X

hal-01146840
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146840
DOI : 10.1016/j.taap.2015.04.007
PUBMED : 25896968

Éditeur(s) : Blackwell science
Résumé : The prawn Penaeus stylirostris (Stimpson), when fed for 28 days with n-3 highly unsaturated fatty acid (HUFA)-enriched feed pellets, demonstrated an enhanced resistance to variations in environmental parameters (a decrease in temperature and salinity over a 4-day period from 28 degreesC to 17 degreesC and from 35 parts per thousand to 10 parts per thousand respectively) and an improvement in their immune defence potential, i.e. increased agglutination titre of plasma and increased respiratory burst of haemocytes.
Aquaculture Research (1355-557X) (Blackwell science), 2001-02 , Vol. 32 , N. 2 , P. 91-94

Droits : 2001 Blackwell
http://archimer.ifremer.fr/doc/2001/publication-606.pdf
DOI:10.1046/j.1365-2109.2001.00534.x
http://archimer.ifremer.fr/doc/00000/606/

Éditeur(s) : HAL CCSD
Résumé : Version électronique LETTERS TO THE EDITOR
Letter to Editors
https://hal.archives-ouvertes.fr/hal-01074492

hal-01074492
https://hal.archives-ouvertes.fr/hal-01074492

Éditeur(s) : HAL CCSD
Résumé : IPC: C07D 311/60 (2006.01), A61K 31/352 (2006.01), A61P 29/00 (2006.01), A61P 35/00 (2006.01), A61P 37/00 (2006.01), C07D 311/64 (2006.01), C07D 335/06 (2006.01), C07D 407/04 (2006.01), C07D 409/04 (2006.01)
The invention relates to new PI3K/AKT/mTOR inhibitors of formula (I) and their use for the prevention and/or the treatment of a disease selected from the group consisting of: inflammatory diseases, autoimmune diseases, neurodegenerative diseases, cancers, transplant rejection, diseases characterized by a premature aging and tuberous sclerosis.
L'invention concerne de nouveaux inhibiteurs de PI3K/AKT/mTOR, et leur utilisation pour la prévention et/ou le traitement d'une maladie choisie dans le groupe constitué par: des maladies inflammatoires, des maladies auto-immunes, des maladies neurodégénératives, des cancers, un rejet de greffe, des maladies caractérisées par un vieillissement prématuré ou la sclérose tubéreuse.
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01139914

Patent N° : WO 2015044229 / EP 2853530
hal-01139914
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01139914

Éditeur(s) : HAL CCSD American Association for Cancer Research
Résumé : International audience
Homing of CD8+ T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGF-β is responsible for CD103 (αEβ7) integrin induction in activated intraepithelial CD8+ T lymphocytes. However, the interplay between TGF-β and CD103 and their contribution to T-cell infiltration and antitumor activity remain unknown. Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Moreover, TGF-β enhanced CD103-dependent T-cell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (αLβ2) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGF-β bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation thereby initiating integrin inside-out signaling. Collectively, our findings suggest that the abundance of TGF-β in the tumor microenvironment may in fact engage with integrin signaling pathways to promote T-lymphocyte antitumor functions, with potential implications for T-cell-based immunotherapies for cancer
ISSN: 0008-5472

Droits : info:eu-repo/semantics/OpenAccess
hal-01282442
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01282442
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01282442/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01282442/file/TGF%CE%B2%20Signaling%20Intersects%20with%20CD103-boutet2016-final.pdf
DOI : 10.1158/0008-5472.CAN-15-1545

Éditeur(s) : Elsevier
Résumé : Understanding of antimicrobial defence mechanisms of penaeid shrimp should help in the design of efficient strategies for the management and disease control in aquaculture. In this study, we have specifically analysed the expression in circulating hemocytes of antimicrobial peptides (AMPs) encoding genes, such as PEN2 and PEN3, ALF, crustin, lysozyme and a putative cysteine-rich peptide. We evidenced a relationship between the level of expression of some AMPs and the successful response of the shrimp, Litopenaeus stylirostris, to circumvent a pathogenic Vibrio penaeicida infection. Additionally, significant differences in some AMP transcript amounts are evidenced between control, non-selected shrimp line and the third generation breeding of shrimp selected for their survival to natural V. penaeicida infections. On the basis of these results, it will now be of great interest to determine if these AMPs are directly involved in the resistance of shrimp to infection or if they only reflect other acquired defence mechanisms which can confer a resistance. (C) 2008 Elsevier Ltd. All rights reserved.
Molecular Immunology (0161-5890) (Elsevier), 2008-07 , Vol. 45 , N. 12 , P. 3438-3445

Droits : 2008 Elsevier Ltd All rights reserved.
http://archimer.ifremer.fr/doc/2008/publication-4524.pdf
DOI:10.1016/j.molimm.2008.04.002
http://archimer.ifremer.fr/doc/00000/4524/