Jean Gugenheim

CD44 is a key player in non-alcoholic steatohepatitis

BACKGROUND & AIMSnCluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression.nnnMETHODSnThe role of CD44 was evaluated in CD44-/- mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n=30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n=64) were evaluated.nnnRESULTSnLiver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44-/- mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p=0.0008) and correlated with NAFLD activity score (NAS) (p=0.001), ballooning (p=0.003), alanine transaminase (p=0.005) and hepatic CCL2 (p<0.001) and macrophage marker CD68 (p<0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44+ cells. Finally, the soluble form of CD44 increased with severe steatosis (p=0.0005) and NASH (p=0.007).nnnCONCLUSIONnHuman and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH.nnnLAY SUMMARYnHuman and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy.

076 Accumulation de cellules dendritiques dans le tissu adipeux en fonction de l’obésité et de l’insulino-résistance chez la souris et les patients

Introduction La regulation des cellules T dans le tissu adipeux constitue un lien important entre l’inflammation et l’insulino-resistance. Nous avons recherche les cellules presentatrices d’antigenes dans le tissu adipeux des souris et patients obeses en fonction de l’insulino-resistance. Patients et methodes Les cellules dendritiques ont ete etudiees dans le tissu adipeux de souris minces, obeses (HFD), Rag1–/–, de 20 patients avec des IMC allant de 19,5 a 38xa0kg/m2, ainsi que des patients obeses morbides sans (nxa0=xa010) ou avec un diabete de type 2 (nxa0=xa0110) par des approches de cytometrie en flux et PCR quantitative Resultats Chez la souris mince, la presence des CDs residantes (CD11chighF4/80neg) est detectee dans le tissu adipeux epididymaire. Chez des souris deficientes en cellules T, le transfert adoptif de cellules T naive specifique a l’ovalbumine induit majoritairement une reponse de type Th1 en reponse a l’ovalbumine dans le tissu adipeux. Dans les souris et patients obeses, les CDs (CD11c+CD1c+ chez l’homme et CD11chighF4/80lowCX3CR1pos chez la souris) sont majoritairement accumulees dans le tissu adipeux. Les CDs CD11chighF4/80low isolees chez les souris obeses induisent, ex-vivo, la polarisation des cellules T naives en cellules Th17. Dans une cohorte de 20 patients, le nombre de cellules CD1c+CD11c+ par g de tissu adipeux sous-cutanes est correle a IMC (rsxa0=xa010,4947; Pxa0 Conclusion Nous montrons, pour la premiere fois, la presence et l’accumulation des CDs dans le tissu adipeux en fonction de l’obesite et de l’insulino-resistance chez la souris et les patients. Ces cellules dendritiques sont fonctionnelles et pourraient favoriser la polarisation des cellules T en Th1 et Th17 dans le tissu adipeux inflamme.