Background & Aims
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.
Methods
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.
Results
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).
Conclusion
Human and experimental data suggest that CD44 is a marker and key player of hepatic
inflammation and its targeting partially corrects NASH.
Lay summary
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.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
Author names in bold designate shared co-first authorship
- Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84
- Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes.Proc Natl Acad Sci U S A. 2012; 109: 7049-7054
- CD44 plays a critical role in regulating diet-induced adipose inflammation, hepatic steatosis, and insulin resistance.PLoS One. 2013; 8: e58417
- Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice.Diabetes. 2015; 64: 867-875
- CCR2 and CD44 promote inflammatory cell recruitment during fatty liver formation in a lithogenic diet fed mouse model.PLoS One. 2013; 8: e65247
- The receptor CD44 is associated with systemic insulin resistance and proinflammatory macrophages in human adipose tissue.Diabetologia. 2015; 58: 1579-1586
- Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity.Diabetes. 2009; 58: 125-133
- Osteopontin: Versatile modulator of liver diseases.Hepatol Res. 2014; 44: 22-30
- Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients.PLoS One. 2010; 5: e13577
- CD44 is a physiological E-selectin ligand on neutrophils.J Exp Med. 2005; 201: 1183-1189
- Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation.Immunol Res. 2014; 58: 186-192
- Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin.Hepatology. 2013; 58: 1814-1823
- Interactions between CD44 and Hyaluronan in Leukocyte Trafficking.Front Immunol. 2015; 6: 68
- Hyaluronic Acid: from biochemical characteristics to its clinical translation in assessment of liver fibrosis.Hepat Mon. 2013; 13: e13787
- The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease.PLoS One. 2012; 7: e35612
- Serum markers of hepatocyte death and apoptosis are non invasive biomarkers of severe fibrosis in patients with alcoholic liver disease.PLoS One. 2011; 6: e17599
- Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH.Gastroenterology. 2006; 131: 788-796
- The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, Type 2 diabetes, and NASH.Am J Gastroenterol. 2006; 101: 1824-1833
- Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing th17 responses in mice and patients.Diabetes. 2012; 61: 2238-2247
- Use and abuse of HOMA modeling.Diabetes Care. 2004; 27: 1487-1495
- Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321
- Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice.Cell Death Dis. 2014; 5: e1208
- Osteopontin modulates CD44-dependent chemotaxis of peritoneal macrophages through G-protein-coupled receptors: evidence of a role for an intracellular form of osteopontin.J Cell Physiol. 2004; 198: 155-167
- Increased macrophage migration into adipose tissue in obese mice.Diabetes. 2012; 61: 346-354
- Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings.Hepatology. 2011; 53: 810-820
- Role of adipose tissue in methionine-choline-deficient model of non-alcoholic steatohepatitis (NASH).Biochim Biophys Acta. 2014; 1842: 959-970
- Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone.Lab Invest. 2007; 87: 56-65
- Requirement for CD44 in activated T cell extravasation into an inflammatory site.Science. 1997; 278: 672-675
- Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G1310-G1321
- Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.Gut. 2012; 61: 416-426
- Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.Hepatology. 2011; 53: 106-115
- Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin alpha(V)beta(3) engagement and PI3K/pAkt/NFkappaB signaling.Hepatology. 2012; 55: 594-608
- Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.Gut. 2015; 64: 1120-1131
- Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis.Biochim Biophys Acta. 2016; 1862: 135-144
- Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury.Gut. 2016; https://doi.org/10.1136/gutjnl-2015-310752
- Non-alcoholic steatohepatitis in morbidly obese patients.Clin Res Hepatol Gastroenterol. 2013; 37: 17-29
- Monocyte chemoattractant protein-1 deficiency does not affect steatosis or inflammation in livers of mice fed a methionine-choline-deficient diet.Lab Invest. 2010; 90: 1794-1804
- Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis.Clin Sci (Lond). 2012; 123: 459-471
- Macrophage heterogeneity in liver injury and fibrosis.J Hepatol. 2014; 60: 1090-1096
- Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress.Drug Metab Pharmacokinet. 2011; 26: 30-46
- M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.Hepatology. 2014; 59: 130-142
- Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance.Diabetes. 2010; 59: 347-357
- Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.Hepatology. 2003; 37: 343-350
- The treatment with antibody of TNF-alpha reduces the inflammation, necrosis and fibrosis in the non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet.Inflammation. 2008; 31: 91-98
- Roles for chemokines in liver disease.Gastroenterology. 2014; 147: 577-594e571
- Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2.J Hepatol. 2006; 44: 1167-1174
- Circulating standard CD44 isoform in patients with liver disease: relationship with other soluble adhesion molecules and evaluation of diagnostic usefulness.Clin Biochem. 1997; 30: 69-73
- Hyaluronan facilitates transforming growth factor-beta1-dependent proliferation via CD44 and epidermal growth factor receptor interaction.J Biol Chem. 2011; 286: 17618-17630
- Transforming growth factor-beta1 (TGF-beta1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts.J Biol Chem. 2013; 288: 14824-14838
Article info
Publication history
Published online: March 18, 2017
Accepted:
March 2,
2017
Received in revised form:
February 1,
2017
Received:
May 27,
2016
Identification
Copyright
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
