Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner

Diego Adhemar Jaitin; Lorenz Adlung; Christoph A. Thaiss; Assaf Weiner; Baoguo Li; Hélène Descamps; Patrick Lundgren; Camille Bleriot; Zhaoyuan Liu; Aleksandra Deczkowska; Hadas Keren-Shaul; Eyal David; Niv Zmora; Shai Meron Eldar; Nir Lubezky; Oren Shibolet; David A. Hill; Mitchell A. Lazar; Marco Colonna; Florent Ginhoux; Hagit Shapiro; Eran Elinav; Ido Amit

doi:10.1016/j.cell.2019.05.054

Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner

Diego Adhemar Jaitin, Lorenz Adlung, Christoph A. Thaiss, Assaf Weiner, Baoguo Li, Hélène Descamps, Patrick Lundgren, Camille Bleriot, Zhaoyuan Liu, Aleksandra Deczkowska, Hadas Keren-Shaul, Eyal David, Niv Zmora, Shai Meron Eldar, Nir Lubezky, Oren Shibolet, David A. Hill, Mitchell A. Lazar, Marco Colonna, Florent GinhouxHagit Shapiro, Eran Elinav^*, Ido Amit

^*Corresponding author for this work

Surgery

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Abstract

Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2⁺ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.

Original language	English
Pages (from-to)	686-698.e14
Journal	Cell
Volume	178
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2019.05.054
State	Published - 25 Jul 2019

Funding

Funders	Funder number
Helen and Martin Kimmel
Thompson Family Foundation
Helmholtz Association
Penn Institute for Immunology
Gilead Sciences
National Institutes of Health
International Progressive MS Alliance
Wolfson Foundation
Leona M. and Harry B. Helmsley Charitable Trust
Children's Hospital of Philadelphia
Global Probiotics Council
Bill and Melinda Gates Foundation
Canadian Institute for Advanced Research
European Research Council
Achelis Foundation
Ludwig-Maximilians-Universität München
Howard Hughes Medical Institute
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK019525, K08DK116668, R01DK049780, P30DK050306, P30DK056341
Diabetes Research Center	P30-DK-019525, P30 NIH DK19525
National Institute of Arthritis and Musculoskeletal and Skin Diseases	P30AR069589
Melanoma Research Alliance	509044
NATIONAL MULTIPLE SCLEROSIS SOCIETY	PA-1604-08459
Horizon 2020 Framework Programme	819439, 724471
Penn Center for Molecular Studies in Digestive and Liver Diseases	P30-DK-050306
Israel Science Foundation	703/15
NeuroMac DFG/Transregional	MS Alliance/NMSS PA-1604-08459
Penn Skin Biology and Diseases Resource-based Center, University of Pennsylvania	P30-AR-069589

Keywords

Alzheimer disease
Trem2 pathway
fatty liver diseases
immunology
macrophages
metabolic diseases
metabolism
obesity
single-cell genomics
systems biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2019.05.054

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Jaitin, D. A., Adlung, L., Thaiss, C. A., Weiner, A., Li, B., Descamps, H., Lundgren, P., Bleriot, C., Liu, Z., Deczkowska, A., Keren-Shaul, H., David, E., Zmora, N., Eldar, S. M., Lubezky, N., Shibolet, O., Hill, D. A., Lazar, M. A., Colonna, M., ... Amit, I. (2019). Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell, 178(3), 686-698.e14. https://doi.org/10.1016/j.cell.2019.05.054

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title = "Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner",

abstract = "Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.",

keywords = "Alzheimer disease, Trem2 pathway, fatty liver diseases, immunology, macrophages, metabolic diseases, metabolism, obesity, single-cell genomics, systems biology",

author = "Jaitin, {Diego Adhemar} and Lorenz Adlung and Thaiss, {Christoph A.} and Assaf Weiner and Baoguo Li and H{\'e}l{\`e}ne Descamps and Patrick Lundgren and Camille Bleriot and Zhaoyuan Liu and Aleksandra Deczkowska and Hadas Keren-Shaul and Eyal David and Niv Zmora and Eldar, {Shai Meron} and Nir Lubezky and Oren Shibolet and Hill, {David A.} and Lazar, {Mitchell A.} and Marco Colonna and Florent Ginhoux and Hagit Shapiro and Eran Elinav and Ido Amit",

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year = "2019",

month = jul,

day = "25",

doi = "10.1016/j.cell.2019.05.054",

language = "אנגלית",

volume = "178",

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Jaitin, DA, Adlung, L, Thaiss, CA, Weiner, A, Li, B, Descamps, H, Lundgren, P, Bleriot, C, Liu, Z, Deczkowska, A, Keren-Shaul, H, David, E, Zmora, N, Eldar, SM , Lubezky, N , Shibolet, O, Hill, DA, Lazar, MA, Colonna, M, Ginhoux, F, Shapiro, H, Elinav, E & Amit, I 2019, 'Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner', Cell, vol. 178, no. 3, pp. 686-698.e14. https://doi.org/10.1016/j.cell.2019.05.054

TY - JOUR

T1 - Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner

AU - Jaitin, Diego Adhemar

AU - Adlung, Lorenz

AU - Thaiss, Christoph A.

AU - Weiner, Assaf

AU - Li, Baoguo

AU - Descamps, Hélène

AU - Lundgren, Patrick

AU - Bleriot, Camille

AU - Liu, Zhaoyuan

AU - Deczkowska, Aleksandra

AU - Keren-Shaul, Hadas

AU - David, Eyal

AU - Zmora, Niv

AU - Eldar, Shai Meron

AU - Lubezky, Nir

AU - Shibolet, Oren

AU - Hill, David A.

AU - Lazar, Mitchell A.

AU - Colonna, Marco

AU - Ginhoux, Florent

AU - Shapiro, Hagit

AU - Elinav, Eran

AU - Amit, Ido

PY - 2019/7/25

Y1 - 2019/7/25

N2 - Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.

AB - Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.

KW - Alzheimer disease

KW - Trem2 pathway

KW - fatty liver diseases

KW - immunology

KW - macrophages

KW - metabolic diseases

KW - metabolism

KW - obesity

KW - single-cell genomics

KW - systems biology

UR - http://www.scopus.com/inward/record.url?scp=85069726280&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2019.05.054

DO - 10.1016/j.cell.2019.05.054

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 31257031

AN - SCOPUS:85069726280

SN - 0092-8674

VL - 178

SP - 686-698.e14

JO - Cell

JF - Cell

IS - 3

ER -

Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner

Abstract

Funding

Keywords

UN SDGs

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