Publications

Publications 2019 – Partner 5

  • Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils. https://www.ncbi.nlm.nih.gov/pubmed/31492810?dopt=Abstract Icon for HighWire Related Articles

    Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils.

    J Exp Med. 2019 Sep 06;:

    Authors: Ohayon D, De Chiara A, Dang PM, Thieblemont N, Chatfield S, Marzaioli V, Burgener SS, Mocek J, Candalh C, Pintard C, Tacnet-Delorme P, Renault G, Lagoutte I, Favier M, Walker F, Hurtado-Nedelec M, Desplancq D, Weiss E, Benarafa C, Housset D, Marie JC, Frachet P, El-Benna J, Witko-Sarsat V

    Abstract
    Neutrophils produce high levels of reactive oxygen species (ROS) by NADPH oxidase that are crucial for host defense but can lead to tissue injury when produced in excess. We previously described that proliferating cell nuclear antigen (PCNA), a nuclear scaffolding protein pivotal in DNA synthesis, controls neutrophil survival through its cytosolic association with procaspases. We herein showed that PCNA associated with p47phox, a key subunit of NADPH oxidase, and that this association regulated ROS production. Surface plasmon resonance and crystallography techniques demonstrated that the interdomain-connecting loop of PCNA interacted directly with the phox homology (PX) domain of the p47phox. PCNA inhibition by competing peptides or by T2AA, a small-molecule PCNA inhibitor, decreased NADPH oxidase activation in vitro. Furthermore, T2AA provided a therapeutic benefit in mice during trinitro-benzene-sulfonic acid (TNBS)-induced colitis by decreasing oxidative stress, accelerating mucosal repair, and promoting the resolution of inflammation. Our data suggest that targeting PCNA in inflammatory neutrophils holds promise as a multifaceted antiinflammatory strategy.

    PMID: 31492810 [PubMed - as supplied by publisher]

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  • Mucosal-associated invariant T cells and disease. https://www.ncbi.nlm.nih.gov/pubmed/31308521?dopt=Abstract Icon for Nature Publishing Group Related Articles

    Mucosal-associated invariant T cells and disease.

    Nat Rev Immunol. 2019 Jul 15;:

    Authors: Toubal A, Nel I, Lotersztajn S, Lehuen A

    Abstract
    Mucosal-associated invariant T (MAIT) cells are unique innate-like T cells that bridge innate and adaptive immunity. They are activated by conserved bacterial ligands derived from vitamin B biosynthesis and have important roles in defence against bacterial and viral infections. However, they can also have various deleterious and protective functions in autoimmune, inflammatory and metabolic diseases. MAIT cell involvement in a large spectrum of pathological conditions makes them attractive targets for potential therapeutic approaches.

    PMID: 31308521 [PubMed - as supplied by publisher]

  • Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis. https://www.ncbi.nlm.nih.gov/pubmed/31188634?dopt=Abstract Icon for Atypon Related Articles

    Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis.

    Am J Physiol Gastrointest Liver Physiol. 2019 Aug 01;317(2):G182-G194

    Authors: Brol MJ, Rösch F, Schierwagen R, Magdaleno F, Uschner FE, Manekeller S, Queck A, Schwarzkopf K, Odenthal M, Drebber U, Thiele M, Lingohr P, Plamper A, Kristiansen G, Lotersztajn S, Krag A, Klein S, Rheinwalt KP, Trebicka J

    Abstract
    Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing.NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development.

    PMID: 31188634 [PubMed - in process]

  • Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis. https://www.ncbi.nlm.nih.gov/pubmed/30941129?dopt=Abstract Icon for Frontiers Media SA Icon for PubMed Central Related Articles

    Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis.

    Front Immunol. 2019;10:476

    Authors: Trebicka J, Amoros A, Pitarch C, Titos E, Alcaraz-Quiles J, Schierwagen R, Deulofeu C, Fernandez-Gomez J, Piano S, Caraceni P, Oettl K, Sola E, Laleman W, McNaughtan J, Mookerjee RP, Coenraad MJ, Welzel T, Steib C, Garcia R, Gustot T, Rodriguez Gandia MA, Bañares R, Albillos A, Zeuzem S, Vargas V, Saliba F, Nevens F, Alessandria C, de Gottardi A, Zoller H, Ginès P, Sauerbruch T, Gerbes A, Stauber RE, Bernardi M, Angeli P, Pavesi M, Moreau R, Clària J, Jalan R, Arroyo V

    Abstract
    Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5-2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating "full-blown" systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.

    PMID: 30941129 [PubMed - in process]

  • Autophagy in liver diseases: Time for translation? https://www.ncbi.nlm.nih.gov/pubmed/30711404?dopt=Abstract Icon for Elsevier Science Related Articles

    Autophagy in liver diseases: Time for translation?

    J Hepatol. 2019 May;70(5):985-998

    Authors: Allaire M, Rautou PE, Codogno P, Lotersztajn S

    Abstract
    Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.

    PMID: 30711404 [PubMed - in process]

  • Orchestration of Tryptophan-Kynurenine Pathway, Acute Decompensation, and Acute-on-Chronic Liver Failure in Cirrhosis. https://www.ncbi.nlm.nih.gov/pubmed/30521097?dopt=Abstract Icon for Wiley Related Articles

    Orchestration of Tryptophan-Kynurenine Pathway, Acute Decompensation, and Acute-on-Chronic Liver Failure in Cirrhosis.

    Hepatology. 2019 Apr;69(4):1686-1701

    Authors: Clària J, Moreau R, Fenaille F, Amorós A, Junot C, Gronbaek H, Coenraad MJ, Pruvost A, Ghettas A, Chu-Van E, López-Vicario C, Oettl K, Caraceni P, Alessandria C, Trebicka J, Pavesi M, Deulofeu C, Albillos A, Gustot T, Welzel TM, Fernández J, Stauber RE, Saliba F, Butin N, Colsch B, Moreno C, Durand F, Nevens F, Bañares R, Benten D, Ginès P, Gerbes A, Jalan R, Angeli P, Bernardi M, Arroyo V, CANONIC Study Investigators of the EASL Clif Consortium, Grifols Chair and the European Foundation for the Study of Chronic Liver Failure (EF Clif)

    Abstract
    Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.

    PMID: 30521097 [PubMed - in process]

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