Resolvin D1 reduces inflammation in co-cultures of primary human macrophages and adipocytes by triggering macrophages

Paulina Wawrzyniak,Syndi Tran,Mattia Schmid,Ivan Hartling,Claudio Gemperle,Martin Hersberger,Nicole Rimann,Jacqueline Marti-Jaun

doi:10.1016/j.plefa.2021.102363

Paulina Wawrzyniak, Syndi Tran + Show 6 more

Open Access

https://doi.org/10.1016/j.plefa.2021.102363

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Abstract

Obesity leads to chronic inflammation of the adipose tissue which is tightly associated with the metabolic syndrome, type 2 diabetes and cardiovascular disease. Inflammation of the adipose tissue is mainly characterized by the presence of crown-like structures composed of inflammatory macrophages in the neighborhood of adipocytes. Resolvin D1 (RvD1), a potent anti-inflammatory and pro-resolving lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid, has been shown to reduce the inflammatory tone of adipose tissue in animal models but the underlying mechanism is not clear. We investigated the effect of RvD1 on the inflammatory state of a human co-culture system of adipocytes and macrophages. For this, human mesenchymal stem cells were differentiated into mature adipocytes and overlaid with human primary macrophages. In this co-culture, 10–500 nM RvD1 dose-dependently reduced the secretion of the pro-inflammatory cytokine IL-6 (-21%) and its soluble receptor IL-6Rα (-22%), of the chemokine MCP-1 (-13%), and of the adipokine leptin (-22%). Similarly, we observed a reduction in secretion of the soluble receptor IL-6Rα (-20%), and TNF-α (-11%) when macrophages alone were treated with RvD1, while no change of cytokine secretion was observed when adipocytes were treated with RvD1. We conclude that RvD1 polarizes macrophages to an anti-inflammatory phenotype, which in turn modulates inflammation in adipocytes.

Highlights

Obesity is associated with chronic, low-grade inflammation, which is recognized as a critical factor for the development of the metabolic syndrome, diabetes and chronic inflammatory diseases like cardiovas cular disease [1, 2, 3]
Application of Resolvin D1 (RvD1) to mice and to adipose tissue explants led to an increase in the secretion of adipo nectin and to a reduction of the secretion of leptin and the pro-inflammatory adipokines TNF-α, IL-6 and IL-1β [19, 21]
To characterize the individual contribution of human macrophages and adipocytes to the elevated adipokine secretion observed in inflamed adipose tissue, we initially measured the secretion of a set of adipokines in individual cell cultures of primary human macrophages and human mesenchymal stem cells (MSC) derived adi pocytes

Summary

Introduction

Obesity is associated with chronic, low-grade inflammation, which is recognized as a critical factor for the development of the metabolic syndrome, diabetes and chronic inflammatory diseases like cardiovas cular disease [1, 2, 3]. There is evidence that the white adipose tissue can expand several times in obese individuals and that this enlarged adipose tissue secretes higher amounts of pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6 [11, 12]. This increased secretion of adipokines is associated with infiltration of immune cells in the obese adipose tissue [5]. Macro phages accumulate in the adipose tissue acting as scavengers of dead adipocytes [3, 13, 14] These macrophages contribute to the cyto kine release of the adipose tissue and to the local and systemic low-grade inflammation. While in non-obese mouse models, non-phlogistic M2 macrophages are ubiquitously present in adipose tissues between adipocytes, dietary obesity induces M1 macrophage recruitment into fat clustering around dead adipocytes (crown-like structures), where they induce inflamma tion and insulin resistance [15]

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