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J Immunol. 2016 Oct 15;197(8):3360-3370. Epub 2016 Sep 19.

Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue.

Author information

1
Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain; esther.titos@ciberehd.org jclaria@clinic.ub.es.
2
Biomedical Research Networking Center on Liver and Digestive Diseases, Barcelona 08036, Spain.
3
Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain.
4
Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
5
European Foundation for the Study of Chronic Liver Failure, Barcelona 08036, Spain.
6
Department of Gastrointestinal Surgery, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain; and.
7
Department of Biomedical Sciences, University of Barcelona, Barcelona 08036, Spain.

Abstract

Persistent activation of the innate immune system greatly influences the risk for developing metabolic complications associated with obesity. In this study, we explored the therapeutic potential of the specialized proresolving mediator (SPM) resolvin D1 (RvD1) to actively promote the resolution of inflammation in human visceral adipose tissue from obese (Ob) patients. Using liquid chromatography-tandem mass spectrometry-based metabololipidomic analysis, we identified unbalanced production of SPMs (i.e., D- and E-series resolvins, protectin D1, maresin 1, and lipoxins) with respect to inflammatory lipid mediators (i.e., leukotriene B4 and PGs) in omental adipose tissue from Ob patients. In parallel, high-throughput transcriptomic analysis revealed a unique signature in this tissue that was characterized by overactivation of the IL-10 signaling pathway. Incubation of inflamed Ob visceral adipose tissues and human macrophages with RvD1 limited excessive activation of the IL-10 pathway by reducing phosphorylation of STAT proteins. Of interest, RvD1 blocked STAT-1 and its target inflammatory genes (i.e., CXCL9), as well as persistent STAT3 activation, without affecting the IL-10 anti-inflammatory response characterized by inhibition of IL-6, IL-1β, IL-8, and TNF-α. Furthermore, RvD1 promoted resolution by enhancing expression of the IL-10 target gene heme oxygenase-1 by mechanisms dependent on p38 MAPK activity. Together, our data show that RvD1 can tailor the quantitative and qualitative responses of human inflamed adipose tissue to IL-10 and provide a mechanistic basis for the immunoresolving actions of RvD1 in this tissue. These findings may have potential therapeutic implications in obesity-related insulin resistance and other metabolic complications.

PMID:
27647830
PMCID:
PMC5101161
DOI:
10.4049/jimmunol.1502522
[Indexed for MEDLINE]
Free PMC Article

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