TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

Phillip West, et al. Nature 472, 476–480 (April 2011)

Speaker: Yin-Chiou, Luo (羅尹秋)                               Time:15:00~16:00, Oct.12, 2011

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍老師)       Place: Room 601

Abstract

Following infection, pathogens are sensed by Pattern-Recognition Receptors, and then are engulfed and killed by phagocytes. Phagocytosis is associated with the production of ROS, necessary components against intracellular bacteria. Although ROS are primarily produced by the NADPHoxidase system in phagocytes, recent studies have indicated that mitochondrial ROS (mROS) also contribute to bactericidal activity. However, the mechanisms linking innate immune signaling and mROS generation remain unclear. Toll-like receptors (TLRs) play an important role in recognizing pathogens. Therefore the authors hypothesized that TLR signaling regulates mROS production and augments macrophage bactericidal activity. First, the authors demonstrated that cell surface TLRs (TLR1/2/4) signaling induces mROS generation and recruits mitochondria to phagosomes. Base on the above data, the authors hypothesized that phagosomes and mitochondria should be regulated by the TLR signaling components. TRAF6 is an important regulator in TLR1/2/4 signaling, and it interacts with ECSIT, a protein localized predominantly to mitochondria and functioned in complex I assembly. They revealed that TRAF6 was recruited to mitochondria and associated with ECSIT. In addition, they provided the evidence indicating that TRAF6-ECSIT signaling regulates the generation of mROS. Furthermore, the authors tested the functional significance of these findings. They used S. typhimurium, an intracellular pathogen that is sensitive to ROS-dependent killing, to infect ECSIT-deficient macrophages, and showed ECSIT-deficient macrophages are less effective at clearing S. typhimurium than WT macrophages. Thus, this study provides evidence for TLR signaling regulating mROS generation and augmenting phagocyte bactericidal activity.

References:

1.      A. Phillip West, et al. Mitochondria in innate immune responses. Nature Reviews Immunology 11, 389-402 (June 2011)