title: 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 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.
authors.affiliation: Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Gupta
authors.affiliation: 1] Laboratory of Immunopathology, NIAID, National Institutes of Health, 5640 Fishers Lane, Room 1421, Rockville, Maryland 20852, USA [2] Department of Food and Nutrition, Seoul National University, Seoul 151-742, Korea.
authors.forename: Dong-Mi
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Ramakrishna
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Goussetis
authors.affiliation: 1] Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, USA [2] Division of Hematology-Oncology, Jesse Brown VA Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.affiliation: Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Laboratory of Immunopathology, NIAID, National Institutes of Health, 5640 Fishers Lane, Room 1421, Rockville, Maryland 20852, USA.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.affiliation: Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008089:Listeria monocytogenes; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D025801:Ubiquitin / Q000737:chemistry; D000099185:Interferon Regulatory Factor-8
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D000099185:Interferon Regulatory Factor-8; C101343:Sqstm1 protein, mouse