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

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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 the 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.

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Gupta, M., Shin, D. M., Ramakrishna, L., Goussetis, D. J., Platanias, L. C., Xiong, H., … Ozato, K. (2015). IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes. Nature Communications, 6. https://doi.org/10.1038/ncomms7379

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