Inhibition of mTOR reduces lipotoxic cell death in primary macrophages through an autophagy-independent mechanism

Li He, Kassandra J. Weber, Abhinav Diwan, Joel D. Schilling

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Macrophage dysfunction in obesity and diabetes is associated with persistent inflammation and poor wound healing responses. Relevant to these phenotypes, we have previously shown that macrophage activation in a high-fat environment results in cell death via a mechanism that involves lysosome damage. While searching for signaling pathways that were required for this response, we discovered that mTOR inhibitors, torin and rapamycin, were protective against lipotoxic cell death in primary peritoneal macrophages. The protective effect of mTOR inhibition was also confirmed by using genetic loss-of-function approaches. Given the importance of mTOR in regulation of autophagy we hypothesized that this pathway would be important in protection from cell death. We first demonstrated that autophagy was disrupted in response to palmitate and LPS as a consequence of impaired lysosome function. Conversely, the mTOR inhibitor, torin, increased macrophage autophagy and protected against lysosome damage; however, the beneficial effects of torin persisted in autophagydeficient cells. Inhibition of mTOR also triggered nuclear localization of TFEB, a transcription factor that regulates lysosome biogenesis and function, but the rescue phenotype did not require the presence of TFEB. Instead, we demonstrated that mTOR inhibition reduces mitochondrial oxidative metabolism and attenuates the negative effects of palmitate on LPS-induced mitochondrial respiration. These results suggest that inhibition of mTOR is protective against lipotoxicity via an autophagyindependent mechanism that involves relieving mitochondrial substrate overload. On the basis of these findings, we suggest that therapies to reduce macrophage mTOR activation may protect against dysfunctional inflammation in states of overnutrition, such as diabetes.

Original languageEnglish
Pages (from-to)1113-1124
Number of pages12
JournalJournal of Leukocyte Biology
Volume100
Issue number5
DOIs
StatePublished - Nov 2016

Keywords

  • Diabetes
  • Lysosome
  • Metabolism
  • TFEB
  • TLRs

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