Treatment with a DC-SIGN ligand reduces macrophage polarization and diastolic dysfunction in the aging female but not male mouse hearts

Joann Trial,George E Taffet,Rodrigo Diaz Lankenau,Aude Angelini,Mark L Entman,Katarzyna A Cieslik,Jorge E Tovar Perez

doi:10.1007/s11357-020-00255-4

Joann Trial, George E Taffet + Show 5 more

Open Access

https://doi.org/10.1007/s11357-020-00255-4

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Abstract

Cardiac diastolic dysfunction in aging arises from increased ventricular stiffness caused by inflammation and interstitial fibrosis. The diastolic dysfunction contributes to heart failure with preserved ejection fraction (HFpEF), which in the aging population is more common in women. This report examines its progression over 12 weeks in aging C57BL/6J mice and correlates its development with changes in macrophage polarization and collagen deposition.Aged C57BL/6J mice were injected with dendritic cell–specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) ligand 1 (DCSL1, an anti-inflammatory agent) or saline for 12 weeks. Echo and Doppler measurements were performed before and after 4 and 12 weeks of treatment. DCSL1 prevented the worsening of diastolic dysfunction over time in females but not in males. Cardiac single cell suspensions analyzed by flow cytometry revealed changes in the inflammatory infiltrate: (1) in males, there was an increased total number of leukocytes with an increased pro-inflammatory profile compared with females and they did not respond to DCSL1; (2) by contrast, DCSL1 treatment resulted in a shift in macrophage polarization to an anti-inflammatory phenotype in females. Notably, DCSL1 preferentially targeted tumor necrosis factor-α (TNFα+) pro-inflammatory macrophages. The reduction in pro-inflammatory macrophage polarization was accompanied by a decrease in collagen content in the heart.Age-associated diastolic dysfunction in mice is more severe in females and is associated with unique changes in macrophage polarization in cardiac tissue. Treatment with DCSL1 mitigates the changes in inflammation, cardiac function, and fibrosis. The characteristics of diastolic dysfunction in aging female mice mimic similar changes in aging women.

Highlights

In clinical studies, heart failure with preserved ejection fraction (HFpEF) in older women is preceded by left ventricular diastolic dysfunction [42]
We previously studied inflammation and fibrosis in the aging male mouse heart [12, 13, 50], and we reported chronic interstitial fibrosis caused by an elevated infiltration of monocytes that later transition into profibrotic macrophages
The dysregulated, low-level chronic cardiac inflammation by macrophages that is persistent in aging is dependent on monocyte chemoattractant protein-1 (MCP-1), which is upregulated in the aging heart [11], and on interleukin-6 (IL-6) [14]

Summary

Introduction

Heart failure with preserved ejection fraction (HFpEF) in older women is preceded by left ventricular diastolic dysfunction [42]. We previously studied inflammation and fibrosis in the aging male mouse heart [12, 13, 50], and we reported chronic interstitial fibrosis caused by an elevated infiltration of monocytes that later transition into profibrotic macrophages. These became collagenproducing cells (“fibrocytes,” which we termed “myeloid fibroblasts,” which correspond to cells previously known as “M2” macrophages). In the aging heart, the interaction between the myeloid-derived fibroblast/pro-fibrotic polarized macrophage and the mesenchymal fibroblast is essential for collagen expression and deposition and if not prevented or reduced may contribute to interstitial fibrosis and diastolic dysfunction.

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