Plasticité du phénotype neuroendocrinien dans les cellules immunitaires

La maturation endoprotéolytique est une modification post-traductionnelle fondamentale. Chez les Eucaryotes, la famille des prohormones convertases PC permet la diversification et la régulation de leurs produits géniques. Parmi les sept membres de cette famille, PC2 et PC1/3 sont connus pour être uniquement exprimées dans le système neuroendocrinien. Leur expression au niveau du système immunitaire est peu connue et les mécanismes régissant leur régulation et leur fonction dans ce système ne sont pas définis. L'analyse dans les conditions physiologiques de leur distribution, a révélé que seule PC1/3 est présente dans les macrophages spléniques. Après un challenge infectieux, l'expression de PC2 et PC1/3 est induite dans les lymphocytes B spléniques. L'induction de la pro-enképhaline après LPS et la détection de peptides dérivant de sa conversion ont permis de mettre en évidence un complexe enzyme substrat fonctionnel dans la rate. Nous avons ensuite choisi la lignée cellulaire de macrophages alvéolaires de rat NR8383 et y avons caractérisé l'expression et la localisation subcellulaire de PC1/3. Dans ces cellules, PC1/3 se présente sous trois formes moléculaires de 110, 90 et 75 kDa. L'activation différentielle des voies de l'immunité innée via les récepteurs Toll-like TLR4 et TLR9 in vitro, nous a permis de démontrer que seule l'exposition à l'ADN CpG aboutit à des modifications du trafic intracellulaire de PC1/3. Nous avons confirmé par immunodétection, la colocalisation de PC1/3 avec le TLR9 dans les mêmes endosomes et lysosomes. Le clivage du TRL9 après le traitement avec de l'ADN CpG suggère donc un nouveau mécanisme d'activation de TLR9 par l'action de PC1/3.LILLE1-BU (590092102) / SudocSudocFranceF

The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3

Induction of type I IFNs is a fundamental cellular response to both viral and bacterial infection. The role of the transcription factor IRF3 is well established in driving this process. However, equally as important are cellular mechanisms for turning off type I IFN production to limit this response. In this respect, IRF3 has previously been shown to be targeted for ubiquitin-mediated degradation postviral detection to turn off the IFN-beta response. In this study, we provide evidence that the E3 ligase Ro52 (TRIM21) targets IRF3 for degradation post-pathogen recognition receptor activation. We demonstrate that Ro52 interacts with IRF3 via its C-terminal SPRY domain, resulting in the polyubiquitination and proteasomal degradation of the transcription factor. Ro52-mediated IRF3 degradation significantly inhibits IFN-beta promoter activity, an effect that is reversed in the presence of the proteasomal inhibitor MG132. Specific targeting of Ro52 using short hairpin RNA rescues IRF3 degradation following polyI:C-stimulation of HEK293T cells, with a subsequent increase in IFN-beta production. Additionally, shRNA targeting of murine Ro52 enhances the production of the IRF3-dependent chemokine RANTES following Sendai virus infection of murine fibroblasts. Collectively, this demonstrates a novel role for Ro52 in turning off and thus limiting IRF3-dependent type I IFN production by targeting the transcription factor for polyubiquitination and subsequent proteasomal degradation

Activation of liver X receptor suppresses the production of the IL-12 family of cytokines by blocking nuclear translocation of NF-kBp50

There is now convincing evidence that liver X receptor (LXR) is an important modulator of the inflammatory response; however, its mechanism of action remains unclear. This study aimed to examine the effect of LXR on the IL-12 family of cytokines and examined the mechanism by which LXR exerted this effect. We first demonstrated that activation of murine-derived dendritic cells (DC) with a specific agonist to LXR enhanced expression of LXR following activation with LPS, suggesting a role in inflammation. Furthermore, we showed LXR expression to be increased in vivo in dextrane sulphate sodium-induced colitis. LXR activation also suppressed production of IL-12p40, IL-12p70, IL-27 and IL-23 in murine-derived DC following stimulation with LPS, and specifically targeted the p35, p40 and EBI3 subunits of the IL-12 cytokine family, which are under the control of the NF-kB subunit p50 (NF-kBp50). Finally, we demonstrated that LXR can associate with NF-kBp50 in DC and that LXR activation prevents translocation of the p50 subunit into the nucleus. In summary, our study indicates that LXR can specifically suppress the IL-12 family of cytokines though its association with NF-kBp50 and highlights its potential as a therapeutic target for chronic inflammatory diseases

Dossier : Femmes, famille et droit

Quelle place occupent les femmes aujourd’hui ? Comment déchiffrer les dynamiques politiques et les conservatismes propres à chacun des pays de la région ? Le dossier, coordonné par Karima Dirèche-Slimani, s’attache à décrypter les évolutions de mœurs et de mentalités à l’œuvre dans les sociétés maghrébines à partir des codes de la famille. Une analyse riche et pertinente. Car si le Maroc tend à consacrer l’égalité juridique entre homme et femme depuis 2004, l’Algérie demeure plus réservée en la matière. Quant à la Tunisie, elle a célébré en 2006 le cinquantenaire du code de statut personnel abolissant la polygamie et la répudiation. Un dossier essentiel qu’accompagnent, à côté des habituels Gros Plans, Notes, Points de vue, Rubriques d’analyse, Études thématiques, des sujets à la pointe de l’actualité : qu’en est-il du pouvoir médiatique au Maghreb ? Qu’en est-il des Maghrébins en Europe ? Éric Gobe, rédacteur en che

Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

International audienceThe aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed