CD11c-MHC2low Macrophages Are a New Inflammatory and Dynamic Subset in Murine Adipose Tissue.

Suzan Wetzels,Erwin Wijnands,Mitchell Bijnen,Casper G Schalkwijk,Susan Coort,Kristiaan Wouters,Andika Tan,Erik A L Biessen,José Van De Gaar

doi:10.20900/immunometab20200015

Abstract

BackgroundThe prevalence of obesity is rising and leads to increased morbidity and mortality. Adipose tissue inflammation, due to accumulation and activation of adipose tissue macrophages (ATMs), is a key driver of this phenomenon. Macrophages are heterogeneous cells, adapting quickly to the microenvironment, resulting in so-called M1 or M2 macrophages. In this study, we describe the dynamics and inflammatory properties of a newly identified ATM subset in obese mice.MethodsLDLR-/- mice received a high fat diet (HFD) for 5 weeks or 16 weeks to induce obesity. Adipose tissues were isolated and immune cell subsets were analyzed with flow cytometry or microarray analysis. Bone marrow transplantation (BMT) using CD45.1 and CD45.2 LDLR-/- mice was performed to determine ATM origin.ResultsUpon HFD, there is a massive increase of ATM subsets in the adipose tissue. CD11c−M2 ATMs could be subdivided based on their MHC2 expression into CD11c−MHC2high ATMs and previously unidentified CD11c−MHC2low ATMs. CD11c−MHC2low ATMs accumulated very rapidly after 10 days of HFD, after which they increased even further with prolonged HFD. Microarray data showed that CD11c−MHC2low ATMs resembled CD11c−MHC2high ATMs in the steady state, but became more inflammatory during development of obesity. In vitro stimulation of bone marrow-derived macrophages with palmitate, abundantly present in HFD, resulted in the induction of the CD11c−MHC2low phenotype.ConclusionsAmong M2 macrophages, a novel pro-inflammatory subset of macrophages was found based on their low level of MHC2 expression. This subset may play a role in the development of adipose tissue inflammation.

Highlights

The ever-rising prevalence of obesity represents one of the major problems in modern health care and healthy aging
CD11c−MHC2low Adipose Tissue Macrophages Are a Novel and Dynamic Subpopulation of Macrophages in the Adipose Tissue of low-density lipoprotein receptor (LDLR)−/− Mice visceral adipose tissue (vAT) isolated from LDLR−/− mice receiving a high fat diet (HFD) for 16 weeks was prepared for flow cytometry and stromal vascular cells were assessed for F4/80, the classical murine macrophage marker and CD11c, which is discriminative for M1 adipose tissue macrophages (ATMs) [15]
All three ATM subsets, F4/80highCD11c−MHC2low, F4/80highCD11c−MHC2high, and F4/80intCD11c+Cd11bhigh cells were decreased in the vAT of obese LDLR−/− mice whereas the F4/80−CD11c+CD11blow dendritic cells remained unaffected showing the phagocytic capacity of the three ATM subsets and confirming their macrophage identity (Supplemental Figure S2)

Summary

Introduction

The ever-rising prevalence of obesity represents one of the major problems in modern health care and healthy aging. Obesity predisposes to “cardiometabolic” diseases like type 2 diabetes (T2D) [1], nonalcoholic fatty liver disease (NAFLD) [2], and to atherosclerotic plaque formation and vascular dysfunction leading to cardiovascular disease (CVD) [3]. Together, these conditions account for the majority of morbidity and mortality in the world. It is widely accepted that inflammation induced by adipose tissue macrophages (ATMs) is a key driver of these conditions [4,5,6,7]. We describe the dynamics and inflammatory properties of a newly identified ATM subset in obese mice

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