CD44 is a key player in non-alcoholic steatohepatitis.
Cluster 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.



The 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.



Liver 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).



Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH.



Human 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.
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France.
Stéphanie
S
Patouraux
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France.
Déborah
D
Rousseau
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France.
Stéphanie
S
Bonnafous
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France.
Cynthia
C
Lebeaupin
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France.
Carmelo
C
Luci
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France.
Clémence M
CM
Canivet
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France.
Anne-Sophie
AS
Schneck
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France.
Adeline
A
Bertola
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France.
Marie-Christine
MC
Saint-Paul
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France.
Antonio
A
Iannelli
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France.
Jean
J
Gugenheim
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France.
Rodolphe
R
Anty
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France.
Albert
A
Tran
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France.
Béatrice
B
Bailly-Maitre
INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France. Electronic address: philippe.gual@inserm.fr.
Philippe
P
Gual
D000328:Adult; D000818:Animals; D050110:Bariatric Surgery; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009767:Obesity, Morbid / Q000097:blood / Q000378:metabolism / Q000601:surgery; D015854:Up-Regulation
D015415:Biomarkers; C497483:CD44 protein, human; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors
CD44; Liver; MCP1; Macrophages; NAFLD; NASH; Steatosis