IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes

Abstract

Autophagy, activated by many stresses, plays a critical role in innate immune responses. Here we show that Interferon Regulatory Factor 8 (IRF8) is required for expression of autophagy-related genes in dendritic cells. Furthermore in macrophages, IRF8 is induced by multiple autophagy-inducing stresses, including IFNγ and toll like receptor stimulation, bacterial infection, starvation and by macrophage colony-stimulating factor. IRF8 directly activates many genes involved in various steps of autophagy, promoting autophagosome formation and lysosomal fusion. Consequently, Irf8-/- macrophages are deficient in autophagic activity, and excessively accumulate SQSTM1 and ubiquitin-bound proteins. We show that clearance of Listeria monocytogenes in macrophages requires IRF8-dependent activation of autophagy genes and subsequent autophagic capturing and degradation of Listeria antigens. These processes are defective in Irf8-/- macrophages where uninhibited bacterial growth ensues. Together, these data suggest that IRF8 is a major autophagy regulator in macrophages, essential for macrophage maturation, survival and innate immune responses.

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

“…Our results for the first time show that AGEs could stimulate M1 polarized macrophage by inducing autophagy. In our study, we further identify that AGEs induced autophagy and M1 polarization through activation of IRF8, which is a regulator of autophagy25, which contributes to delayed wound healing. Specific inhibition of IRF8 resulted in reduction of autophagy and less M1 polarization in cells and finally ameliorated wound healing in mice.…”

“…Those results indicate that IRF8 and autophagy are downstream of AGEs stimulation. In addition, in light of the importance of IRF8 in stress-activated autophagy in Ozato’s study25, it is tempting to postulate that IRF8 is regulating AGEs-induced autophagy. To investigate the involvement of IRF8 in our study, we designed an IRF8-specific shRNA that could reduce the IRF8 protein level of 70%.…”

Passive immunization with anti-ActA and anti-listeriolysin O antibodies protects against Listeria monocytogenes infection in mice

“…Therefore, anti-ActA antibody may not only disturb actin polymerization, but also may promote localization of intracytosolic L. monocytogenes with autophagosomes. Clearance of intracellular L. monocytogenes mediated by these antibodies might be involved in autophagy because recent studies reported that autophagy is induced by IFN-γ and TNF-α stimulation and restricts intracellular growth of L. monocytogenes 2728. However, anti-ActA antibody alone also could not provide a completely protective effect, suggesting that only defect of actin tail is not enough for listerial clearance.…”

Checks and Balances between Autophagy and Inflammasomes during Infection

“…Mice harboring Atg5 −/− -deficient monocyte/macrophages and granulocytes had increased L. monocytogenes burden and decreased survival [63]. Also, C57BL/6 irf8 −/− mice displayed increased L. monocytogenes burden due to lower levels of autophagy, and it was proposed that the transcription factor IRF8 downstream from IFNγ controls the expression of seven of the autophagy genes during Listeria infection [64]. The autophagy adaptor optineurin is phosphorylated by the TANK binding kinase 1, which enhances its affinity for LC3 and L. monocytogenes degradation by autophagy in HeLa cells in an LLO-dependent fashion [65].…”