Brown adipose tissue monocytes support tissue expansion

Alexandre Gallerand,Jérôme Gilleron,Stoyan Ivanov,Narges Khedher,David Dombrowicz,Pascal Barbry,Hannah Luehmann ,Laurent Yvan‐Charvet ,Deborah Sultan ,Rodolphe Guinamard ,Maria Firulyova ,Adélie Dumont ,Marion I Stunault,Johanna Merlin,Bastien Dolfi,Marion Ayrault,Yongjian Liu,Burkhard Becher,David Masson,Virginie Magnone,Alexia Castiglione,Jesse W Williams,Antoine Jalil,Nathalie Vaillant,Matthias Mack,Thomas Bertero,Konstantin Zaitsev

doi:10.1038/s41467-021-25616-1

Abstract

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.

Highlights

Monocytes are part of the mononuclear phagocytic system
This brown adipose tissue (BAT) macrophage subset diversity might reflect their involvement in various functions from lipid handling (Clusters 6, 7, and 8) to tissue remodeling (Cluster 5)
We found that monocytes intensely contribute to BAT macrophage maintenance

Summary

Introduction

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. Podoplanin engagement is strictly required for BAT expansion Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling. 8 Institute of Experimental Immunology, University of Zürich, Monocytes are part of the mononuclear phagocytic system together with macrophages and dendritic cells (DCs)[1] These cells are generated in the bone marrow compartment where they originate from hematopoietic stem cells (HSC) through myelopoiesis, a tightly regulated process[2]. We used an established mouse model of adipocyteselective Atgl-deficiency leading to BAT expansion and evaluated monocyte numbers in bone marrow and blood, and monocyte and macrophage numbers and diversity in adipose tissues. Our data show that monocytes contribute to BAT expansion in a Podoplanin-dependent mechanism and favor matrix remodeling, uncovering a new function for this cell type

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Conclusion