Therapeutic targeting of adipose tissue macrophages ameliorates liver fibrosis in non-alcoholic fatty liver disease
Celia Martínez–Sánchez, Octavi Bassegoda, Hongping Deng, Xènia Almodóvar, Ainitze Ibarzábal, Ana de Hollanda, R. La Torre, Delia Blaya, Sílvia Ariño, Natalia Jiménez, Beatriz Aguilar‐Bravo, Júlia Vallverdú, Carla Montironi, Óscar Osorio-Conles, Yiliam Fundora, Francisco Javier Sánchez Moreno, Alícia G. Gómez-Valadés, Laia Aguilar-Corominas, Anna Sòria, Elisa Pose, Adrià Juanola, Marta Cervera, Martina Pérez, Virginia Hernández–Gea, Silvia Affò, Kelly S. Swanson, Joana Ferrer, José M. Balibrea, Pau Sancho‐Bru, Josép Vidal, Pere Ginès, Andrew M. Smith, Isabel Graupera, Mar Coll
Abstract
Background and aimsThe accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the ATMs contribution to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in NAFLD patients and evaluate the impact of ATMs modulation over hepatic fibrosis in an experimental NASH model.MethodsAdipose tissue and liver biopsies from 42 NAFLD patients with different fibrosis stages were collected. ATMs were characterized by immunohistochemistry and flow cytometry and correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of ATMs phenotype was achieved by ip administration of dextran coupled with dexamethasone in diet induced obese and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSC) and liver spheroids was performed.ResultsNAFLD patients presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSC and liver spheroids.ConclusionsPro-inflammatory ATMs increase in parallel with fibrosis degree in NAFLD patients and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD.Impact and implicationsWe report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in NAFLD. Furthermore, the modulation of adipose tissue macrophages by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATM to an anti-inflammatory phenotype in an experimental murine model of NASH. This shift ameliorates adipose tissue inflammation, hepatic inflammation and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.