Consequences and significance of TAK1 inhibition in macrophages

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Macrophages are essential cells for tissue maintenance and mediating inflammation, and they reside ubiquitously throughout the body. Macrophages are primary phagocytic cells that engulf and destroy pathogens, parasites and any unwanted material. However, some pathogens actively invade macrophages to subvert and thwart macrophage defense. The pathogen-derived mechanisms to evade macrophage defense include disrupting the immune response. Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is a key intermediate molecule of the intracellular inflammatory signaling pathways, and is, therefore, one of the major targets of immune disruption by pathogens. It has been known that disruption of TAK1 not only blocks inflammatory signaling but also triggers activation of two types of cell death pathways, i.e. apoptosis and necroptosis. However, the biological significance of TAK1 inhibition-induced cell death pathways has been obscure. I found that inhibition of TAK1 activates these pathways and limits intracellular bacterial growth in macrophages. Most notably, it is associated with increases of mitochondrial reactive oxygen species (ROS). I hypothesize that mitochondrial ROS are a mediator of the macrophage defense against bacterial inhibition of TAK1. I aim to; i) characterize the effects of mitochondrial ROS induced by TAK1 inhibition on bacterial growth and mitochondrial homeostasis; ii) elucidate the mechanisms through which TAK1 regulates mitochondrial ROS. Outcomes of this project would yield novel understanding of TAK1 function, macrophage biology and host defense mechanisms.