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

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 (MΦTSC2-/-) mice were generated by crossing Lys2Cre with TSC2flx/flx. In vitro, bone marrow-derived MΦTSC2-/- 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. MΦTSC2-/- 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 MΦTSC2-/- myocardium had fewer pro-inflammatory (CCR2+MHC-IIhi) 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 MΦTSC2-/- 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.