Human CD206+ macrophages associate with diabetes and adipose tissue lymphoid clusters.

Lindsey A Muir,Niko Kaciroti,Nicki A Baker,Scott Ronquist,Carmen G Flesher,Indika Rajapakse,Kae Won Cho,Anne P Ehlers,Lynn M Geletka,Robert W O’Rourke,Carey N Lumeng,Stephen Lindsly

doi:10.1172/jci.insight.146563

Abstract

Increased adipose tissue macrophages (ATMs) correlate with metabolic dysfunction in humans and are causal in development of insulin resistance in mice. Recent bulk and single-cell transcriptomics studies reveal a wide spectrum of gene expression signatures possible for macrophages that depends on context, but the signatures of human ATM subtypes are not well defined in obesity and diabetes. We profiled 3 prominent ATM subtypes from human adipose tissue in obesity and determined their relationship to type 2 diabetes. Visceral adipose tissue (VAT) and s.c. adipose tissue (SAT) samples were collected from diabetic and nondiabetic obese participants to evaluate cellular content and gene expression. VAT CD206+CD11c− ATMs were increased in diabetic participants, were scavenger receptor–rich with low intracellular lipids, secreted proinflammatory cytokines, and diverged significantly from 2 CD11c+ ATM subtypes, which were lipid-laden, were lipid antigen presenting, and overlapped with monocyte signatures. Furthermore, diabetic VAT was enriched for CD206+CD11c− ATM and inflammatory signatures, scavenger receptors, and MHC II antigen presentation genes. VAT immunostaining found CD206+CD11c– ATMs concentrated in vascularized lymphoid clusters adjacent to CD206–CD11c+ ATMs, while CD206+CD11c+ were distributed between adipocytes. Our results show ATM subtype–specific profiles that uniquely contribute to the phenotypic variation in obesity.

Highlights

Obesity remains a significant public health concern, contributing to risk of cardiovascular disease, type 2 diabetes mellitus (DM), and adverse outcomes in viral infection [1]
Within PTPRC+ (CD45+) Stromal vascular cells (SVCs), we identified CD64+ adipose tissue macrophages (ATMs) and ATM subtypes CD206+CD11c− (CD206+), CD206+CD11c+, and CD206−CD11c+ (CD11c+), as well as CD64−CD11c+ adipose tissue DCs (ATDCs) (Figure 1, A and B); this was accomplished using a stratification approach justified by prior literature and findings in mice [5, 9, 11]
Total ATMs had similar frequency in Visceral adipose tissue (VAT) and s.c. adipose tissue (SAT) of obese participants (Table 1), but differences were observed for ATM subtypes (Figure 1, C and D; endothelial cells were greater in VAT)

Summary

Introduction

Obesity remains a significant public health concern, contributing to risk of cardiovascular disease, type 2 diabetes mellitus (DM), and adverse outcomes in viral infection [1]. Adipose tissue dysfunction in obesity contributes to the development of metabolic disease. With long-term HFD feeding, macrophages and DCs contribute to inflammation and dysregulated tissue remodeling related to metabolic dysfunction [3,4,5]. Skewed proportions of adipose tissue macrophage (ATM) subtypes, such as increased proinflammatory ITAX+ (CD11c+) ATMs, contribute to insulin resistance in mice [4], but the role of human ATMs and subtypes in obesity remains unclear. Human ATMs increase in obesity, and a proinflammatory type is reported to correlate with metabolic dysfunction, though various M1-like, M2-like, and mixed M1/M2 phenotypes have been observed [6,7,8,9,10], complicating stratification and interpretation of their function in human adipose tissue

Methods

Results

Conclusion