The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction.

Ingmar Sören Meyer,Florian Leuschner,Felix Lasitschka,Andreas Jungmann,Stefan E Hardt,Oliver J Müller,Michael Boutros,Susann Werkmeister,Hugo A Katus,Jan Haas,Christoph Dieterich,Matthias Nahrendorf,Min Zhang

doi:10.15252/emmm.201707565

Ingmar Sören Meyer, Florian Leuschner + Show 11 more

Open Access

https://doi.org/10.15252/emmm.201707565

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Abstract

A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment‐dependent changes in inflammatory monocytes after MI. RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes—but not fibroblasts or endothelial cells—upon hypoxia. Compared to wild‐type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI. While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV‐mediated cardiomyocyte‐specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control‐AAV‐treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non‐canonical WNT signaling and led to reduced IL‐1β and IL‐6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non‐canonical WNT signaling shifts the accumulating myeloid cells toward a pro‐inflammatory state and impacts healing after myocardial infarction.

Highlights

Myocardial infarction (MI) is one of the leading causes of death in industrialized nations
RNA-seq analyses revealed that MI results in a diverse transcriptional response in inflammatory monocytes sorted from the bone marrow (BM), blood, and heart
Our findings suggest that upon accumulation, leukocytes are locally adjusted by WNT modulators actively secreted by cardiomyocytes

Summary

Introduction

Myocardial infarction (MI) is one of the leading causes of death in industrialized nations. Following acute coronary occlusion and subsequent myocardial damage, neutrophils are the first dominant leukocyte subset to invade the infarcted heart. Their numbers peak early, during the first days after cardiac injury, and monocytes and their lineagedescendant macrophages become the predominant infiltrating cell types over the course of the first week (Swirski & Nahrendorf, 2013). The monocyte/macrophage response is biphasic: Whereas pro-inflammatory Ly-6Chi monocytes dominate the early phase (1–4 days post-injury), reparative Ly-6Clo macrophages are the predominant cell type at later stages (Nahrendorf et al, 2007; Hilgendorf et al, 2014; He et al, 2015). The inflammatory Ly-6Chi monocytes are highly proteolytic and phagocytotic They clear dead a 2017 The Authors.

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