Objective Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c+ proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development.
Design vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr-/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH.
Results Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c+ and CD11c− macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c+ ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes.
Conclusion ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment.
- non-alcoholic steatohepatitis
- immunology in hepatology
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Contributors MB performed experiments, analysed the data and wrote the manuscript. TJ and IC performed experiments and analysed data. CJM, MV and JvdG performed experiments. EW contributed to flow cytometry experimental design and measurements. SSR collected human tissue samples and analysed human microarray data. JWMG performed bariatric surgery. MHH collected and analysed human microarray data. EALB supervised flow cytometry design and measurements. CDAS and CGS supervised experiments and revised the manuscript. KW designed the study, performed experiments, analysed the data, supervised experiments and wrote the manuscript.
Funding This study was financed by The Netherlands Organization for Scientific Research (NWO) (Veni 916.12.056), The Netherlands Heart Foundation (2013T143) and a Seventh Framework Program (FP7) Grant (CIG 322070) to KW.
Competing interests None declared.
Ethics approval Medical Ethics Board of Maastricht University Medical Centre.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it published Online First. A citation for supplementary figures 1 and 2 has been added as well as the files.