TY - JOUR
T1 - IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes
AU - Gupta, Monica
AU - Shin, Dong Mi
AU - Ramakrishna, Lakshmi
AU - Goussetis, Dennis J.
AU - Platanias, Leonidas C.
AU - Xiong, Huabao
AU - Morse, Herbert C.
AU - Ozato, Keiko
N1 - Funding Information:
We thank K.-T. Jeang, H.-S. Wang, S. Bradfute, V. Nagarajan, K.-A. McDonough and H. Yoshii for advice and critical reading of the manuscript. This work was supported by the Intramural Program of NICHD and NIAID, National Institutes of Health and NIH grants CA77816 and CA121192.
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/4/23
Y1 - 2015/4/23
N2 - 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.
AB - 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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U2 - 10.1038/ncomms7379
DO - 10.1038/ncomms7379
M3 - Article
C2 - 25775030
AN - SCOPUS:84928568291
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 6379
ER -