Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice
Open accessAbstract
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.
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In mice fed a high fat, high cholesterol-containing diet, adipose tissue macrophages exacerbated liver damage by enhancing neutrophil recruitment to the liver.
“Interaction between neutrophils and extrahepatic immune cells is also of concern in MASH; in mice fed with a high fat, high cholesterol-containing diet, adipose tissue macrophages exacerbated liver damage by enhancing neutrophil recruitment to the liver(232).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [232]
The AT transplantation section distinguishes high-fat-fed adipose-tissue donors from acceptor mice fed a high-cholesterol diet; it does not describe the liver-damage experiment as mice fed a combined high-fat, high-cholesterol diet. The Discussion reports ATM-dependent hepatic neutrophil recruitment and increased liver-enzyme levels suggesting damage, but presents the proposed sequence from neutrophil recruitment to liver damage as possible rather than established. (LLM, conf=0.86)
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- Authors
- Bijnen, M., Josefs, T., Cuijpers, I., Maalsen, C. J., van de Gaar, J., Vroomen, M., Wijnands, E., Rensen, S. S., Greve, J. W. M., Hofker, M. H., Biessen, E. A. L., Stehouwer, C. D. A., Schalkwijk, C. G., & Wouters, K.
- Affiliations
- Maastricht University Medical Centre (NL)
- Department of Internal Medicine, MUMC, Maastricht, Limburg, The Netherlands
- Atrium Medisch Centrum Parkstad (NL)
- University Medical Center Groningen (NL)
- Corresponding author
- Wouters, Kristiaan
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2017-10-26
- Volume
- 67
- Issue
- 7
- Pages
- 1317-1327
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2765415318
- Cited by
- 134
- References
- 37
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 10 · 2023: 17 · 2022: 16 · 2021: 21 · 2020: 26 · 2019: 12 · 2018: 9 · 2017: 1
- FWCI
- 10.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Hartstichting
- Seventh Framework Programme
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- adipose tissue macrophages, nonalcoholic steatohepatitis, obesity, neutrophil recruitment, neutrophil chemotaxis, CXCL14, CXCL16, clodronate liposome depletion, liver inflammation, CD11c
- MeSH terms
- Adipose Tissue, Animals, Liver, Macrophages, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Cytokines, CD11 Antigens, Neutrophil Infiltration, Mice, Non-alcoholic Fatty Liver Disease
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