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

Nature Communications
Monica GuptaKeiko Ozato

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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Citations

Jul 30, 2015·Autophagy·Romana T Netea-MaierMihai G Netea
Jun 16, 2015·Frontiers in Immunology·Leslie Chávez-GalánIrene Garcia
Apr 24, 2018·FEBS Letters·Ryota OudaKeiko Ozato
Jul 28, 2018·European Journal of Oral Sciences·Bo W NilsenKaren K Sørensen
Sep 4, 2019·Nature Communications·Yu-Kuan HuangAlex Boussioutas
Jan 21, 2016·Oncotarget·Hongming PanXinbing Sui
Jun 9, 2017·Scientific Reports·Yuri AhnDo-Young Kim
Sep 12, 2018·Proceedings of the National Academy of Sciences of the United States of America·Rui KamadaKeiko Ozato
Mar 17, 2021·Journal of Leukocyte Biology·Lindsey DevisscherHans Van Vlierberghe
Dec 14, 2018·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Marta CuencaPablo Engel

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Datasets Mentioned

BETA
GSE64666

Methods Mentioned

BETA
lipidation
GTPases
immunoprecipiation
ChIP
flow cytometry
in-vitro transcription
PCR
immunoprecipitation

Software Mentioned

Affymetrix GeneChip Operating Software ( GCOS )
Excel
Expression Console

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