Work

Macrophages lacking TSC2 have mTORC1-dependent increased GPNMB and ameliorate ventricular dysfunction/remodeling after ischemia-reperfusion

Year: 2025

Type: article

Abstract: Macrophages (MΦ) modulate myocardial inflammation and repair after ischemia-reperfusion (I/R) injury. The mechanistic target of rapamycin (mTOR) regulates MΦ phenotype and functionality, but studies conflict regarding its pro- or anti-inflammatory role. To test this, myeloid TSC2 depleted (MΦ TSC2−/− ) mice were generated by crossing Lys2 Cre with TSC2 flx/flx . In vitro, bone marrow-derived MΦ TSC2−/− vs. control MΦ had greater mTORC1 and less mTORC2 activity coupled with differential responses to pro- or anti-inflammatory ligands. These disparities were eliminated by inhibiting mTORC1 with rapamycin. MΦ TSC2−/− mice had substantially less cardiac dysfunction and ventricular remodeling after I/R, with reduced lung edema and activation of stress/pro fibrotic genes. These differences were eliminated by treating mice with rapamycin, supporting mTORC1 dependence. Post I/R MΦ TSC2−/− myocardium had fewer pro-inflammatory (CCR2 + MHC-II hi ) MΦ, LY6C + monocytes, LY6G + neutrophils, and CD8 + T cells at 5-days post-I/R, and fewer CCR2 + but more CCR2 − MΦ 2-wks after I/R. Synthesis of glycoprotein nonmetastatic melanoma protein B (GPNMB), a MΦ secreted anti-inflammatory protein was greater in MΦ TSC2−/− macrophages and myocardium after I/R in an mTORC1 dependent manner. Thus, constitutive mTORC1 activation in MΦ depresses pro-inflammatory cell infiltration, increases GPNMB protein expression, and preserves heart function following I/R. This reveals beneficial effects of a MΦ-dependent mTORC1-GPNMB cascade on the post I/R heart.

Source: Scientific Reports

DOI: 10.1038/s41598-025-24699-w