Abstract
Myocardial infarction (MI) triggers an intense inflammatory response that is essential for dead tissue clearance but also detrimental to cardiac repair. Macrophages are active and critical players in the inflammatory response after MI. Understanding the molecular mechanisms by which macrophage-mediated inflammatory response is regulated is important for designing new therapeutic interventions for MI. In the current study, we examined the role of Sestrin2, which is a stress-inducible protein that regulate metabolic homeostasis, in the regulation of inflammatory response of cardiac macrophages after MI. We found that cardiac macrophages upregulated Sestrin2 expression in a mouse MI model. Using a lentiviral transduction system to overexpress Sestrin2 in polarized M1 and M2 macrophages, we revealed that Sestrin2 predominantly functioned on M1 rather than M2 macrophages. Sestrin2 overexpression suppressed inflammatory response of M1 macrophages both in vitro and in vivo. Furthermore, in the mouse MI model with selective depletion of endogenous macrophages and adoptive transfer of exogenous Sestrin2-overexpressing macrophages, the anti-inflammatory and repair-promoting effect of Sestrin2-overexpressing macrophages was demonstrated. Furthermore, Sestrin2 significantly inhibited mTORC1 signaling in M1 macrophages. Taken together, our study indicates the importance of Sestrin2 for suppression of M1 macrophage-mediated cardiac inflammation after MI.
Highlights
An inflammatory response, which is important for cardiac repair and implicated in the progression of cardiac remodeling and heart failure, is triggered by myocardial infarction (MI) [1]
Only a non-significant increase of Sestrin2 protein was seen in circulating monocytes after MI, suggesting that local factors rather than systemic factors were responsible for the increase of Sestrin2 in macrophages (Figures 1B,C)
Careful analysis of Sestrin2 expression in F4/80hi Ly-6C−, F4/80loLy-6C−, F4/80loLy-6C+, and F4/80hiLy-6C+ subpopulations revealed that Sestrin2 was predominantly expressed in Ly-6C+ macrophages at day 3 after MI (Figure 1D), suggesting that Sestrin2 was closely associated with the pro-inflammatory phenotype of cardiac macrophages
Summary
An inflammatory response, which is important for cardiac repair and implicated in the progression of cardiac remodeling and heart failure, is triggered by myocardial infarction (MI) [1]. The significance of macrophages for the progression and resolution of infarct inflammation, as well as for the tissue healing and remodeling, has been suggested in previous studies using selective depletion of monocytes/macrophages [4, 6, 7]. Due to their crucial role in the pathophysiological processes triggered by MI, monocytes/macrophages represent a potential therapeutic target to promote myocardial repair and functional regeneration. The molecular mechanisms underlying the recruitment and functions of monocytes/macrophages upon the onset of MI have not been thoroughly elucidated
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