Journal
GENES & DEVELOPMENT
Volume 21, Issue 15, Pages 1909-1920Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1553007
Keywords
mitochondria; macrophages; Listeria monocytogenes; oxidative metabolism; reactive oxygen species
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [P30 CA014195] Funding Source: Medline
- NIDDK NIH HHS [U19 DK062434, U19 DK62434-01] Funding Source: Medline
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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-alpha-induced activation of ERR alpha depends on coactivator PGC-1 beta (peroxisome proliferator-activated receptor alpha coactivator-1 beta), which appears to be a direct target for the IFN-alpha/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.
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