Key result
Myocardial injury induces overlapping pro- and anti-inflammatory transcriptional programs in cardiac macrophages, limited by a hypoxia-mediated Il10 negative-feedback loop.
This study provides a core resource for deciphering the in vivo transcriptional network of cardiac macrophages, revealing complex overlapping activation states and regulatory feedback loops after myocardial injury.
No immediate clinical implications for myocardial injury; hypothesis-generating for Il10 modulation in cardiac macrophage responses.
Macrophage plasticity has been studied in vitro, but transcriptional regulation upon injury is poorly understood. We generated a valuable dataset that captures transcriptional changes in the healthy heart and after myocardial injury, revealing a dynamic transcriptional landscape of macrophage activation. Partial deconvolution suggested that post-injury macrophages exhibit overlapping activation of pro-inflammatory and anti-inflammatory programs rather than aligning to canonical M1/M2 programs. Furthermore, simulated dynamics and experimental validation of a regulatory core of the underlying gene-regulatory network revealed a negative-feedback loop that limits initial inflammation via hypoxia-mediated upregulation of Il10. Our results also highlight the prominence of post-transcriptional regulation (miRNAs, mRNA decay, and lincRNAs) in attenuating the myocardial injury-induced inflammatory response. We also identified a cardiac-macrophage-specific gene signature (e.g., Egfr and Lifr) and time-specific markers for macrophage populations (e.g., Lyve1, Cd40, and Mrc1). Altogether, these data provide a core resource for deciphering the transcriptional network in cardiac macrophages in vivo.
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Walter et al. (2018) studied Myocardial injury. Myocardial injury vs. Healthy heart was evaluated on Transcriptional and post-transcriptional changes in macrophages. Myocardial injury induces overlapping pro- and anti-inflammatory transcriptional programs in cardiac macrophages, limited by a hypoxia-mediated Il10 negative-feedback loop.
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