Walter W., Alonso-Herranz L., Trappetti V., Crespo I., Ibberson M., Cedenilla M., Karaszewska A., Núñez V., Xenarios I., Arroyo A.G., Sanchez-Cabo F., Ricote M. Deciphering the dynamic transcriptional and post-transcriptional networks of cardiac macrophages in the healthy heart and after myocardial injury. Cell reports. 2018 Apr 10;23(2):622-636.
Our group is interested in the behavior and transcriptional regulation of macrophages in the context of complex disease environments. We have generated a whole transcriptome dataset (mRNA, miRNA, and lincRNA) of macrophages in the healthy heart and at different stages post-injury, providing an important resource for improving understanding of how macrophages integrate, process, and respond to signals from their local environment.
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.