Single‐cell RNA sequencing reveals the induction of novel myeloid and myeloid‐associated cell populations in visceral fat with long‐term obesity

Abstract

Macrophages and other immune cells are important contributors to obesity‐associated inflammation; however, the cellular identities of these specific populations remain unknown. In this study, we identified individual populations of myeloid cells found in mouse epididymal/visceral adipose tissue by single‐cell RNA sequencing, immunofluorescence, and flow cytometry. Multiple canonical correlation analysis identified 11 unique myeloid and myeloid‐associate cell populations. In obese mice, we detected an increased percentage of monocyte‐derived pro‐inflammatory cells expressing Cd9 and Trem2, as well as significantly decreased percentages of multiple cell populations, including tissue‐resident cells expressing Lyve1, Mafb, and Mrc1. We have identified and validated a novel myeloid/macrophage population defined by Ly6a expression, exhibiting both myeloid and mesenchymal characteristics, which increased with obesity and showed high pro‐fibrotic characteristics in vitro. Our mouse adipose tissue myeloid cell atlas provides an important resource to investigate obesity‐associated inflammation and fibrosis.

Sphingolipid metabolism during Toll‐like receptor 4 (TLR4)‐mediated macrophage activation

“…During cardiovascular pathology, macrophages can differentiate into foam cells rich in cholesterol esters and triglycerides in the arterial wall and undergo Abbreviations: CD, cluster of differentiation; Gb, globoside; GD, disyalicganglioside; GM, monosyalicganglioside; GT, trisyalicganglioside; iGb, isogloboside; TLR4, toll-like receptor 4. dramatic changes in their lipid metabolism (Childs et al, 2016;Stary et al, 1994;Tontonoz et al, 1998). Lipid-associated macrophages (LAMs) are found in white adipose tissue (Hill et al, 2018;Jaitin et al, 2019) and their frequency increases with obesity in mice and humans (Harasymowicz et al, 2021;Hildreth et al, 2021). Infectious diseases also greatly impact macrophage lipid metabolism.…”

Adipoclast: a multinucleated fat-eating macrophage

“…Similarly, CD9, another marker of LAMs [53], was found to colocalize with the pan-macrophage marker CD68 in human WAT [54]. Notably, TREM2+ and CD9+ LAMs were found to be part of CLS [52,53] and their frequency increased with obesity in mice and humans [50,51] with a shift toward a pro-inflammatory polarization characterized by IL-1β and TNF production [51].…”

“…While it is accepted that obesity is associated with a shift toward pro-inflammatory macrophage function [45][46][47], WAT macrophages have a unique polarization state (metabolically activated macrophages [48]) and paradoxically, crown-like structures contain the M2-like marker CD206 (mannose receptor) and CD11c expressing macrophages [49]. Recent single cell transcriptomics studies revealed the different subtypes of adipose tissue macrophages and their evolution upon obesogenic conditions [50][51][52][53][54]. Two markers of white adipose tissue macrophages of particular interest include TREM2 and CD9.…”

Towards in silico Models of the Inflammatory Response in Bone Fracture Healing

“…The importance of the role of macrophages as initiators of the repair phase has been shown by Schlundt et al (2018) , who observed altered endochondral ossification in cases where the macrophages within the fracture site were depleted. Recently, experimental work has shown that macrophage activation is rather like a spectrum than a two-state system, with specific signatures depending on the location within the spectrum ( Mosser and Edwards, 2008 ; Harasymowicz et al, 2021 ).…”