Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense.
Macrophage activation by the proinflammatory cytokine interferon-gamma (IFN-gamma) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-gamma-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-gamma induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERR alpha (estrogen-related receptor alpha, NR3B1). Studies with macrophages lacking ERR alpha demonstrate that it is required for induction of mitochondrial reactive oxygen species (ROS) production and efficient clearance of Listeria monocytogenes (LM) in response to IFN-gamma. As a result, mice lacking ERR alpha are susceptible to LM infection, a phenotype that is localized to bone marrow-derived cells. Furthermore, we found that IFN-gamma-induced activation of ERR alpha depends on coactivator PGC-1 beta (peroxisome proliferator-activated receptor gamma coactivator-1 beta), which appears to be a direct target for the IFN-gamma/STAT-1 signaling cascade. Thus, ERR alpha and PGC-1 beta act together as a key effector of IFN-gamma-induced mitochondrial ROS production and host defense.
Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Junichiro
J
Sonoda
Josée
J
Laganière
Isaac R
IR
Mehl
Grant D
GD
Barish
Ling-Wa
LW
Chong
Xiangli
X
Li
Immo E
IE
Scheffler
Dennis C
DC
Mock
Alain R
AR
Bataille
Francois
F
Robert
Chih-Hao
CH
Lee
Vincent
V
Giguère
Ronald M
RM
Evans
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D008089:Listeria monocytogenes / Q000276:immunology / Q000472:pathogenicity; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D000097983:ERRalpha Estrogen-Related Receptor
D002352:Carrier Proteins; D004247:DNA; D007371:Interferon-gamma; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D000097983:ERRalpha Estrogen-Related Receptor; C455622:PPARGC1B protein, human