Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling

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.

Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

“…Previous studies have shown that sestrin2 inhibited the mTOR complex 1 (mTORC1) signaling pathway, and mTORC1-mediated macrophage phenotype transition and function [ 19 ]. To further confirm the role of mTOR signaling in BV2 cells treated with sestrin2, we treated BV2 cells with an mTOR activator MHY-1485 at the beginning of OGD.…”

“…Furthermore, Sestrin2 has been shown to suppress sepsis in macrophages by inducing mitophagy and inhibiting NLRP3 activation [ 18 ]. Sestrin2 has been shown to regulate the cardiac macrophage-mediated inflammatory response after myocardial infarction by inhibiting the pro-inflammatory response of M1 macrophages [ 19 ]. As “resident macrophages” in the brain, microglia are part of the mononuclear phagocyte system.…”

Macrophage Modification Strategies for Efficient Cell Therapy

“…A study by Yang et al was focused on the role of stress-inducible protein Sestrin2 ( Sesn2 ) in the control of inflammation in myocardial infarction (MI) [ 91 ]. The authors demonstrated a suppressive role of the lentivirus-mediated overexpression of Sestrin2 in pro-inflammatory macrophages in the control of cardiac inflammation after MI both in vitro and in vivo.…”

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

“…Then, all mice were given DOX (Part 4). In a fifth experiment, IL-22-knockout mice were subjected to adoptive transfer of WT macrophages (10 6 cells/mouse) or IL-22-knockout macrophages from the tail vein [ 25 ] and treated with DOX or saline (Part 5). In a final experiment, 3 weeks prior to DOX treatment, both WT mice and IL-22-knockout mice were injected once with AAV9 carrying Recombinant plasmid Gene-IRES-ZsGreen to up-regulate Fizz3 expression (AAV9-Fizz3, Selleck) or negative control AAV9 from the tail vein (Part 5).…”