Presentation

Inflammatory and stress responses in chronic liver diseases

 Sophie Lotersztajn

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Our team studies the mechanisms underlying chronic liver disease progression to cirrhosis and its complications, with an emphasis on the identification of prognosis markers and therapeutic targets for fatty liver diseases.Our research program focuses on the identification of immunometabolic targets and biomarkers of liver and systemic inflammation.

Non-alcoholic and alcoholic fatty liver diseases (NAFLD, ALD) are leading causes of liver diseases worldwide. They share common pathogenic features including steatosis and steatohepatitis (alcoholic-ASH and non-alcoholic-NASH) that lead to fibrosis and cirrhosis. Persistent inflammation is a driving force of liver fibrosis progression during NAFLD and ALD. Among patients with cirrhosis, excessive inflammation results in the development of multiorgan failure (defining acute-on-chronic liver failure, ACLF), which often leads to death. The lack of treatment highlights the urgent need for new prognosis markers and specific therapeutic targets that could limit liver injury, fibrosis, progression of cirrhosis to ACLF, and favour liver regeneration.

Ongoing studies are investigating:

i)     The mechanisms underlying monocyte/macrophage reprogramming and the impact on fatty liver disease progression to fibrosis, and on liver regeneration. We target specific pathways we recently uncovered, including canonical and non canonical autophagy, macrophage apoptosis and lipid metabolic targets such as monoacylglycerol lipase. Lodder Autophagy 2015 Denaes, 2016, Sci Rep, Gual, 2017 AJP, Wan Hepatology 2014, Gandoura J Hepatol 2015, Louvet, Hepatology 2011 Mallat, J Hepatol 2013, Mallat Am J Physiol 2013, Weiss, J Hepatol 2017, Habib Gut 2018

ii)  The role of adaptive immune cells (Th17) and non conventional (Mucosal-associated invariant T (MAIT) cells) T lymphocytes in the control of inflammation at sequential steps of fatty liver progression (Guillot, Hepatology 2014, Hegde Nat Com 2018)

iii)  Novel biomarkers, targets and clinical studies evaluating new therapeutic strategies in NAFLD, cirrhosis and ACLF, a syndrome we characterized and in which systemic inflammation is a major trigger (Moreau, Gastroenterology 2013,Gustot Hepatology 2016, Claria J Hepatol 2016, Claria Hepatology 2018).

Networks : founding team of the European Consortium for the Study of Chronic Liver Failure (EF-CLIF), French-Indian network (LIA)), DHU Unity and RHU QUID.

Funding: Inserm, Université Paris-Diderot, Laboratory of Excellence Inflamex, National research agency (ANR), Fondation pour la Recherche médicale (FRM), french associations for the study of the liver and for digestive diseases (AFEF, SNFGE), Inserm-Transfert, Assistance Publique Hopitaux de Paris (PHRC),


                                                                                                                                                                                                                                                                   

Selected publications
  1. Hegde P, Weiss E, Paradis V, Wan J, Mabire M, Sukriti S, Rautou PE, Albuquerque M, Picq O, Gupta AC, Ferrere G, Gilgenkrantz H, Kiaf B, Toubal A, Beaudoin L, Lettéron P, Moreau R, Lehuen A, Lotersztajn S. Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver. Nat Commun. 2018 Jun 1;9(1):2146.
  2. Habib A, Chokr D, Wan J, Hegde P, Mabire M, Siebert M, Ribeiro-Parenti L, Le Gall M, Lettéron P, Pilard N, Mansouri A, Brouillet A, Tardelli M, Weiss E, Le Faouder P, Guillou H, Cravatt BF, Moreau R, Trauner M, Lotersztajn S. Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver. Gut. 2018 Oct 9. pii: gutjnl-2018-316137. doi: 10.1136/gutjnl-2018-316137. [Epub ahead of print]
  3. Effects of Long-term Norfloxacin Therapy in Patients With Advanced Cirrhosis.Moreau R, Elkrief L, Bureau C, Perarnau JM, Thévenot T, Saliba F, Louvet A, Nahon P, Lannes A, Anty R, Hillaire S, Pasquet B, Ozenne V, Rudler M, Ollivier-Hourmand I, Robic MA, d’Alteroche L, Di Martino V, Ripault MP, Pauwels A, Grangé JD, Carbonell N, Bronowicki JP, Payancé A, Rautou PE, Valla D, Gault N, Lebrec D; NORFLOCIR Trial Investigators.Gastroenterology. 2018 Dec;155(6):1816-1827.May;66(5):930-941
  4. Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, Lotersztajn S, Pavoine C. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology. 2014 Jan;59(1):130-42
  5. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, Gustot T, Saliba F, Domenicali M, Gerbes A, Wendon J, Alessandria C, Laleman W, Zeuzem S, Trebicka J, Bernardi M, Arroyo V; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013 Jun;144(7):1426-37, 1437.e1-9.
Team members

 

Team leader Sophie Lotersztajn, DR
 
Researchers Laurent Castera, PUPH
  François Durand, PUPH
  Claire Francoz, PH 
  Aida Habib, CR
  Philippe Letteron, CR
Hélène Gilgenkrantz, DR
Richard Moreau, DRE
  Catherine Paugam-Burtz, PUPH
  Olivier Soubrane, PUPH
  Dominique Valla, PUPH
  Emmanuel Weiss, MCU-PH
PhD Students  Manon Allaire
Engeneers & technicians  Benjamin Morin, IE
 Morgane Mabire, AI
   Jinghong Wan, IE