TSC1 Regulates TLR4-induced Type Ⅰ Interferons In Macrophages

Macrophages are the major innate immune cells which recognize invaded pathogens through Toll-like receptors,and initiate host defense and repair injuries thereafter.Recent studies have uncovered a critical role of TSC1-m TOR,a major pathway regulating cell metabolism,in the initiation and activation of immune responses.Despite a role of TSC1-m TOR in macrophage differentiation and proinflammatory response has been demonstrated,whether and how it is involved in IFN response has not been reported.In this study,we firstly revealed a critical role of TSC1 in the regulation of TLR4-induced IFN response in macrophages.Mechanistically,TSC1-deficiency led to elevated phosphorylation of IRF3,a transcriptional factor required for IFN induction by LPS stimulation.Furthermore,we also found that the expression of MKP5,a phosphatase for IRF3,was dwonregulated in TSC1-deficient macrophages.Interestingly,re-expression of MKP5 in TSC1-deficient macrophages repressed LPS-induced IFN response,suggesting that TSC1 may regulates IFN response by dwonregulating MKP5.Importantly,our results also indicated that TSC1 may be critically involved in the control of bacteria E.coli-induced IFN and proinflammatory responses in vivo.Collectively,these data identified TSC1 as a pivotal regulator of bacteria-induced IFN response and suggested a novel mechanism by which TSC1 regulates IRF3 activation.