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Profiling of murine resident adipose tissue and aortic macrophages according to their expression status of LYVE-1

ABSTRACT: Beside their role in conventional immune regulation, macrophages are now recognised as essential regulator of local tissue homeostasis depending on the tissue in which they reside. Using phenotyping, we found that LYVE-1+ macrophages are the major resident macrophage population in murine aorta and adipose tissues under steady state. Furthermore, imaging analysis revealed the exclusive association of adipose tissue LYVE-1+ macrophages with smooth muscle positive large blood vessels. Hence, we hypothesize that LYVE-1+ macrophages sustain large vessel functional homeostasis. The present experiment aims to better characterize resident LYVE-1+ vs LYVE-1- macrophages in aorta and adipose tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE114630 | GEO | 2018/06/01

REPOSITORIES: GEO

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Project description:In adult mice, “heart attack” or myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis) and function to drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents oedema and reduces inflammatory/fibrotic immune cell content to improve cardiac function. Given the importance of the adult cardiac lymphatics in macrophage clearance after injury, we investigated their role across the neonatal “regenerative window”. At post-natal day 1 (P1) neonatal mice fully regenerate their heart following MI, in a pro-regenerative macrophage-dependent manner, whereas equivalent injury at post-natal day 7 (P7) leads to scarring driven by pro-fibrotic macrophages. We hypothesised that lymphatics respond and function differently during this “window” to clear macrophage-specific subtypes, depending upon their requirement for regeneration versus fibrotic repair. Normal lymphatic growth and sprouting was evident in intact neonatal hearts until P16, with strain-dependent developmental differences. The response to injury revealed limited lymphangiogenesis (lymphatic vessel growth and sprouting) and minimal clearance of macrophages from P1 compared to P7 infarcted hearts, as determined by adoptive transfer, and monitoring of cleared macrophages to MLNs. This is coincident with maturation of lymphatic endothelial cell junctions across the neonatal period via transition from “zipper” (impermeable) to “button” (permeable) -type junctions and altered signalling between lymphatic endothelial cells and macrophages, including differential expression of the lymphangiocrine factor Reelin (RELN). Finally, in mice lacking the lymphatic endothelial receptor-1 (LYVE-1), that exhibit impaired transmigration of interstitial macrophages to lymphatic vessels, magnetic resonance imaging (MRI) revealed a surprising impaired functional outcome in P1 mice 28 days post-MI. Given our observations that pro-regenerative macrophages at P1 are not trafficked, this suggested a distinct role for LYVE-1 in tissue-resident macrophages, consistent with its expression pattern in developing and post-natal hearts. Macrophage-specific deletion of Lyve1 during neonatal heart injury revealed impaired heart regeneration, characterised by persistent fibrosis, a reduced neovascular response and reduced function. ScRNA-seq of Lyve1 deficient CD45+ cells revealed a loss of tissue-resident macrophages and an increase in recruited monocytes which is predicted to increase inflammation and fibrosis, worsening the outcome post-MI. Collectively, this study reveals that cardiac lymphatics are developmentally compromised for clearance in early neonates, which enables retention of pro-regenerative tissue-resident macrophages, and that LYVE-1 plays an essential role in maintaining this population to promote heart regeneration and prevent inflammation and fibrotic repair.

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Profiling of murine resident adipose tissue and aortic macrophages according to their expression status of LYVE-1

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