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
N1 - Funding Information:
We thank Genia Brodsky from the Scientific Illustration unit of the Weizmann Institute for artwork, Tomer Meir Salame from the Cell Cytometry unit, Calanit Raanan and Marina Cohen for histology, and members of the Amit and Elinav laboratories for discussions. We thank Prof. Christian Haass from the LMU Munich for providing the anti-Trem2 antibody (Xiang et al. 2016). I.A. is supported by the Chan Zuckerberg Initiative (CZI), an HHMI international scholar award, European Research Council consolidator grant (ERC-COG) 724471-HemTree2.0, the Thompson Family Foundation, an MRA established investigator award (509044), the Israel Science Foundation (703/15), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine, a Helen and Martin Kimmel award for innovative investigation, a NeuroMac DFG/Transregional Collaborative Research Center grant, International Progressive MS Alliance/NMSS PA-1604-08459, an Adelis Foundation grant, and the SCA award of the Wolfson Foundation. I.A. is the incumbent of the Alan and Laraine Fischer Career Development Chair. D.A.H. is supported by NIH DK116668 and a CHOP junior faculty grant. M.A.L. is supported by NIH DK49780. D.A.H. and M.A.L. acknowledge The Center for Applied Genomics at the Children's Hospital of Philadelphia and the Human Metabolic Tissue Bank of the Penn Diabetes Research Center (P30 NIH DK19525). C.A.T. is supported by the Edward Mallinckrodt, Jr. Foundation, an Agilent early career professor award, the Global Probiotics Council, and grants from the PennCHOP Microbiome Program, the Penn Institute for Immunology, the Penn Center for Molecular Studies in Digestive and Liver Diseases (P30-DK-050306), the Penn Skin Biology and Diseases Resource-based Center (P30-AR-069589), and the Penn Diabetes Research Center (P30-DK-019525). N.Z. is supported by the Gilead Sciences International Research Scholars Program in Liver Disease. H.S. is supported by The V.R. Schwartz Research Fellow Chair. E.E. is supported by Y. and R. Ungar, the Leona M. and Harry B. Helmsley Charitable Trust, the Adelis Foundation, J.L. and V. Schwartz, D.L. Schwarz, and by grants funded by the European Research Council, the Israel Science Foundation, the Helmholtz Foundation, and the Bill and Melinda Gates Foundation. E.E. is a senior fellow of the Canadian Institute of Advanced Research (CIFAR), and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI). accession, Conceptualization, C.A.T. D.A.J. E.E. and I.A.; Methodology, D.A.J. C.A.T. and I.A.; Investigation, D.A.J. L.A. C.A.T. B.L. C.B. F.G. H.D. P.L. and A.D.; Software, A.W. and L.A.; Formal Analysis, A.W. L.A. D.A.J. C.A.T. and C.B.; Data Curation, A.W. L.A. and E.D.; Writing – Original Draft, D.A.J. L.A. C.A.T. and I.A.; Writing – Review & Editing, D.A.J. C.A.T. F.G. and I.A.; Visualization, D.A.J. A.W. L.A. C.A.T. and B.L.; Funding Acquisition, E.E. and I.A.; Resources, H.S. Z.L. M.C. S.M.E. N.L. O.S. D.A.H, M.A.L. H.K.-S. and N.Z.; Supervision, E.E. and I.A. A patent application has been filed related to this work.
Funding Information:
We thank Genia Brodsky from the Scientific Illustration unit of the Weizmann Institute for artwork, Tomer Meir Salame from the Cell Cytometry unit, Calanit Raanan and Marina Cohen for histology, and members of the Amit and Elinav laboratories for discussions. We thank Prof. Christian Haass from the LMU Munich for providing the anti-Trem2 antibody ( Xiang et al., 2016 ). I.A. is supported by the Chan Zuckerberg Initiative (CZI), an HHMI international scholar award, European Research Council consolidator grant (ERC-COG) 724471-HemTree2.0 , the Thompson Family Foundation , an MRA established investigator award ( 509044 ), the Israel Science Foundation ( 703/15 ), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine , a Helen and Martin Kimmel award for innovative investigation, a NeuroMac DFG/Transregional Collaborative Research Center grant, International Progressive MS Alliance / NMSS PA-1604-08459 , an Adelis Foundation grant, and the SCA award of the Wolfson Foundation . I.A. is the incumbent of the Alan and Laraine Fischer Career Development Chair. D.A.H. is supported by NIH DK116668 and a CHOP junior faculty grant. M.A.L. is supported by NIH DK49780 . D.A.H. and M.A.L. acknowledge The Center for Applied Genomics at the Children's Hospital of Philadelphia and the Human Metabolic Tissue Bank of the Penn Diabetes Research Center ( P30 NIH DK19525 ). C.A.T. is supported by the Edward Mallinckrodt, Jr. Foundation , an Agilent early career professor award, the Global Probiotics Council , and grants from the PennCHOP Microbiome Program , the Penn Institute for Immunology , the Penn Center for Molecular Studies in Digestive and Liver Diseases ( P30-DK-050306 ), the Penn Skin Biology and Diseases Resource-based Center ( P30-AR-069589 ), and the Penn Diabetes Research Center ( P30-DK-019525 ). N.Z. is supported by the Gilead Sciences International Research Scholars Program in Liver Disease . H.S. is supported by The V.R. Schwartz Research Fellow Chair . E.E. is supported by Y. and R. Ungar , the Leona M. and Harry B. Helmsley Charitable Trust , the Adelis Foundation , J.L. and V. Schwartz , D.L. Schwarz , and by grants funded by the European Research Council , the Israel Science Foundation , the Helmholtz Foundation , and the Bill and Melinda Gates Foundation . E.E. is a senior fellow of the Canadian Institute of Advanced Research (CIFAR), and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI). accession
Publisher Copyright:
© 2019 Elsevier Inc.
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 - Article
C2 - 31257031
AN - SCOPUS:85069726280
SN - 0092-8674
VL - 178
SP - 686-698.e14
JO - Cell
JF - Cell
IS - 3
ER -