Cardiac macrophage subsets differentially regulate lymphatic network remodeling during pressure overload

Mathilde Bizou,Estelle Pichery,Dimitri Marsal,Angelo Parini,Dounia Abbadi,Barbara Garmy-Susini,Victorine Douin-Echinard,Mina Majdoubi,Romain Itier,Denis Calise,Nathalie Pizzinat,Jérome Roncalli,Marianne Dutaur

doi:10.1038/s41598-021-95723-y

Mathilde Bizou, Estelle Pichery + Show 11 more

Open Access

PDF Available

https://doi.org/10.1038/s41598-021-95723-y

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking. We observed a remodeling of the cardiac lymphatic vessels and a reduced lymphatic efficiency during heart hypertrophy and failure induced by transverse aortic constriction. The lymphatic endothelial cell number of the failing hearts was positively correlated with cardiac function and with a subset of cardiac macrophages. This macrophage population distinguished by LYVE-1 (Lymphatic vessel endothelial hyaluronic acid receptor-1) and by resident macrophage gene expression signature, appeared not replenished by CCR2 mediated monocyte infiltration during pressure overload. Isolation of macrophage subpopulations showed that the LYVE-1 positive subset sustained in vitro and in vivo lymphangiogenesis through the expression of pro-lymphangiogenic factors. In contrast, the LYVE-1 negative macrophage subset strongly expressed MMP12 and decreased the endothelial LYVE-1 receptors in lymphatic endothelial cells, a feature of cardiac lymphatic remodeling in failing hearts. The treatment of mice with a CCR2 antagonist during pressure overload modified the proportion of macrophage subsets within the pathological heart and preserved lymphatic network from remodeling. This study reports unknown and differential functions of macrophage subpopulations in the regulation of cardiac lymphatic during pathological hypertrophy and may constitute a key mechanism underlying the progression of heart failure.

Highlights

The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking
Monocytes identified as CD45+Ly6G−CD11b+CD64lo cells and a small population of C D45+Ly6G−CD11b+CD64+ MHCIIneg accounting for less than 5% of macrophages, did not express LYVE-1 (Fig. 1A)
The L+ subset revealed gene expression associated with resident macrophages (Fig. 1F) while FLT3, a receptor involved in cell survival of hematopoietic stem cells was more expressed in L− macrophages suggesting that higher number of this subset may result from bone marrow-derived monocyte differentiation (Fig. 1G)[33,34]

Summary

Introduction

The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking. The lymphatic endothelial cell number of the failing hearts was positively correlated with cardiac function and with a subset of cardiac macrophages. This macrophage population distinguished by LYVE-1 (Lymphatic vessel endothelial hyaluronic acid receptor-1) and by resident macrophage gene expression signature, appeared not replenished by CCR2 mediated monocyte infiltration during pressure overload. Monocytes/macrophages have been described as a major group of leukocytes infiltrating the injured hearts where they contribute in exacerbating pathological cardiac remodeling in concert with others immune cells, such as CD4+ T-cells[14,15,16,17]. They take part in the process of healing and restoring tissue homeostasis with potential contributions from regulatory T-cells[18,19]

Methods

Results

Conclusion