Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice

Mitchell Bijnen, Tatjana Josefs, Ilona Cuijpers, Constantijn J. Maalsen, Jose van de Gaar, Maria Vroomen, Erwin Wijnands, Sander S. Rensen, Jan Willem M. Greve, Marten H. Hofker, Erik A. L. Biessen, Coen D. A. Stehouwer, Casper G. Schalkwijk, Kristiaan Wouters*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

67 Citations (Web of Science)
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Abstract

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 (AT M) is an important driver of vAT inflammation. We investigated the role of AT Ms in hepatic inflammation during NASH development.

Design vAT isolated from lean, obese or AT M -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 T ransplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. AT M 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 AT M 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+ AT Ms. 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 AT Ms from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment.

Original languageEnglish
Pages (from-to)1317-1327
Number of pages11
JournalGut
Volume67
Issue number7
DOIs
Publication statusPublished - Jul 2018

Keywords

  • FATTY LIVER-DISEASE
  • NONALCOHOLIC STEATOHEPATITIS
  • INFLAMMATION
  • OBESITY
  • STEATOSIS
  • CELL
  • MONOCYTOSIS
  • ASSOCIATION
  • SUBTYPES
  • ROLES

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