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

Monica Gupta, Dong-Mi Shin, Lakshmi Ramakrishna, Dennis J. Goussetis, Leonidas C. Platanias, Huabao Xiong, Herbert C. Morse and Keiko Ozato ()
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Monica Gupta: Program in Genomics of Differentiation, NICHD, National Institutes of Health
Dong-Mi Shin: Laboratory of Immunopathology, NIAID, National Institutes of Health
Lakshmi Ramakrishna: Program in Genomics of Differentiation, NICHD, National Institutes of Health
Dennis J. Goussetis: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Leonidas C. Platanias: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Huabao Xiong: Immunology Institute, Mount Sinai School of Medicine
Herbert C. Morse: Laboratory of Immunopathology, NIAID, National Institutes of Health
Keiko Ozato: Program in Genomics of Differentiation, NICHD, National Institutes of Health

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7379

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