Prion protein expression and functional importance in developmental angiogenesis: role in oxidative stress and copper homeostasis.

International audienceAIM: It has been convincingly shown that oxidative stress and toxicity by deregulated metals, such as copper (Cu), are tightly linked to the development of pre-eclampsia and intrauterine growth retardation (IUGR), the most threatening pathologies of human pregnancy. However, mechanisms implemented to control these effects are far from being understood. Among proteins that bind Cu and insure cellular protection against oxidative stress is the cellular prion protein (PrP(C)), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrP(C) in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrP(C) knockout mice [PrP(-/-)], and PrP(C) overexpressing mice [Tga20]). RESULTS: At the cellular level, PrP(C) protection against oxidative stress was established in multiple angiogenic processes: proliferation, migration, and tube-like organization. For the animal models, lack (PrP(-/-)) or overexpression (Tga20) of PrP(C) in gravid mice caused severe IUGR that was correlated with a decrease in litter size, changes in Cu homeostasis, increase in oxidative stress response, development of hypoxic environment, failure in placental function, and maintenance of growth defects of the offspring even 7.5 months after delivery. INNOVATION: PrP(C) could serve as a marker for the idiopathic IUGR disease. CONCLUSION: These findings demonstrate the stress-protective role of PrP(C) during development, and propose PrP(C) dysregulation as a novel causative element of IUGR

Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression

The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway

The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease

Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice

BackgroundInfections may be associated with exacerbation of allergic and autoimmune diseases. Paradoxically, epidemiological and experimental data have shown that some microorganisms can also prevent these pathologies. This observation is at the origin of the hygiene hypothesis according to which the decline of infections in western countries is at the origin of the increased incidence of both Th1-mediated autoimmune diseases and Th2-mediated allergic diseases over the last decades. We have tested whether Toll-like receptor (TLR) stimulation can recapitulate the protective effect of infectious agents on allergy and autoimmunity. Methods and Findings Here, we performed a systematic study of the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental models, ovalbumin (OVA)-induced asthma and spontaneous autoimmune diabetes, presenting the same genetic background of the non obese diabetic mouse (NOD) that is highly susceptible to both pathologies. In the same models, we also investigated the effect of probiotics. Additionally, we examined the effect of the genetic invalidation of MyD88 on the development of allergic asthma and spontaneous diabetes. We demonstrate that multiple TLR agonists prevent from both allergy and autoimmunity when administered parenterally. Probiotics which stimulate TLRs also protect from these two diseases. The physiological relevance of these findings is further suggested by the major acceleration of OVA-induced asthma in MyD88 invalidated mice. Our results strongly indicate that the TLR-mediated effects involve immunoregulatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β and different subsets of regulatory T cells, notably CD4+CD25+FoxP3+ T cells for TLR4 agonists and NKT cells for TLR3 agonists. Conclusions/Significance These observations demonstrate that systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies

Séminaire MIMED, février 2023 : présentation de l’Atlas des Migrations dans le Monde (2022) et projection du film 18 mois (2022)

Le jeudi 16 février 2023 sur le Campus Saint-Charles à Marseille (3 place Victor-Hugo, 13001), de 16h à 20h. Lieu : Amphithéâtre des Sciences Naturelles, le bâtiment 8, entrée libre.  Le séminaire sera en deux parties : 16:00 -18:00 présentation de l'Atlas des Migrations dans le Monde (2022), possibilité de suivre à distance : https://univ-amu-fr.zoom.us/j/83900788919?pwd=MGdWNGFNRFF6eTNtU1hQbVphbVpidz09 (ID de réunion : 839 0078 8919 ; code secret : mimed) 18:00-20:00 projection du film 18..

Séminaire Mimed autour de l'ouvrage En transit. Les Syriens à Beyrouth, Marseille, Le Havre, New York (1880-1914)

Le jeudi 20 octobre 2022 de 14h00 à 16h00 à la MMSH (Aix-en-Provence), salle A113. Entrée libre. Intervenante : Céline Regnard, Maîtresse de conférences en histoire moderne, habilitée à diriger des recherches, laboratoire TELEMMe, Aix-Marseille Université. Pour une discussion de son ouvrage En Transit, Les Syriens à Beyrouth, Marseille, Le Havre, New York (1880 - 1914). En transit. Les Syriens à Beyrouth, Marseille, Le Havre, New York (1880-1914), Anamosa, 2022, est un essai historique sur le..

‘Urban, regional, Mediterranean scaling of the construction of Marseille as a ‘welcoming city’ for migrants’,

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Bristol, « ville accueillante » : gouvernance locale, mythe de la « diversité » et leadership du maire

International audienceCet article analyse le processus de construction d’une politique locale d’accueil et d’intégration des populations migrantes, à partir d’une enquête de terrain menée à Bristol en 2020 auprès d’acteurs municipaux, associatifs, privés, universitaires et de citoyens ordinaires. Dans un contexte national britannique hostile à l’immigration et marqué par des mesures d’austérité, cette politique émerge graduellement à la croisée de prises de position municipales, d’engagements associatifs et d’une stratégie de développement du territoire orchestrée par les acteurs publics locaux. En effet, la politique d’accueil de Bristol en tant que « ville accueillante » s’appuie concrètement sur une mobilisation associative financée de plus en plus par le secteur privé, et sur l’engagement de la municipalité. Nous montrons comment, tout en initiant des dispositifs institutionnels temporaires qui s’appuient sur une expertise externe, la municipalité de Bristol mobilise le mythe et l’image d’une ville « cosmopolite » et d’une grande diversité ethnique et culturelle, ainsi que le leadership politique de certains élus sur les questions migratoires, pour faire de Bristol une « ville accueillante »

Les espaces de visibilisation des personnes exilées primo-arrivantes à Marseille

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