Chapter 8 - Role of the Transcription Factor Interferon Regulatory Factor-1 in Regulating Autophagy in Lipopolysaccharide-Stimulated Macrophages

Abstract

The pathogenesis of sepsis is complex and unfortunately poorly understood. The cellular process of autophagy, especially in macrophages, is believed to have multiple important functions in sepsis. Our study demonstrated that, interferon regulatory factor-1 (IRF-1) could regulate the autophagic response in lipopolysaccharide (LPS)-stimulated macrophages. In vivo, tissue macrophages obtained from LPS-stimulated IRF-1 knockout (KO) mice demonstrated increased autophagy and decreased apoptosis compared to those isolated from IRF-1 wild-type (WT) mice. In vitro, LPS-stimulated peritoneal macrophages obtained from IRF-1 KO mice experienced increased autophagy and decreased apoptosis. IRF-1 mediates the inhibition of autophagy by modulating the activation of the mammalian target of rapamycin (mTOR). LPS induced the activation of mTOR in WT peritoneal macrophages, but not in IRF-1 KO macrophages. In contrast, overexpression of IRF-1 alone increased the activation of mTOR and consequently decreased autophagic flux. Furthermore, the inhibitory effects of IRF-1 mTOR activity were mediated by nitric oxide (NO). Therefore we propose a novel role for IRF-1 and NO in the regulation of macrophage autophagy during LPS stimulation, in which IRF-1/NO inhibits autophagy through mTOR activation.