hes multiple TLR-initiated pathways and bactericidal activity of macrophages. TLR1, 2 and 4 activation results in mitochondrial translocation of TRAF6 that interacts with ECSIT, a protein that has been implicated in mitochondrial respiratory complex I assembly, leading to increased mitochondrial ROS that aid in the destruction of phagocytosed bacteria. It is not clear how ECSIT PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19849834 regulates mitochondrial ROS production upon TLR stimulation. Furthermore, patients with tumor necrosis factor receptor-associated periodic syndrome have heightened responsiveness to LPS due to increased mitochondrial ROS production that promotes inflammation. Aside from ROS, the TCA cycle intermediate succinate has also been implicated in LPSinduced inflammatory cytokine signaling. In the TCA cycle, succinate is produced from succinyl-CoA and subsequently converted to fumarate by succinate dehydrogenase. Succinate dehydrogenase is the only TCA enzyme that also functions as an BAY-41-2272 custom synthesis electron carrier in the electron transport chain, which may position it to also modulate ROS signaling. In LPS-activated macrophages, increases in succinate concentrations stabilize HIF-1 through inhibition of PHDs, an effect that has previously been reported to occur in tumors. This stabilization of HIF-1 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Immunity. Author manuscript; available in PMC 2016 March 17. Weinberg et al. Page 6 induces the expression of the pro-inflammatory cytokine IL-1. In addition to directly activating HIF-1 through PHD inactivation, succinate may also increase mROS production, which is known to activate HIF-1 in macrophages. Interestingly, a recent study demonstrated that succinate build up results in increased reverse electron transport and ROS production from complex I of the ETC. Going forward it will be important to decipher the mechanism by which LPS results in accumulation of succinate and whether succinate activation of IL-1 expression requires mitochondrial ROS. Citrate is another TCA cycle intermediate implicated in LPS activation of pro-inflammatory gene expression. It is known that it is exported from the mitochondria to the cytosol and converted to acetyl-CoA, however the precise mechanism by which it thereby alters cytokine production is unclear. In addition to TLRs, other pattern recognition receptors are known to depend on mitochondrial ROS signaling including nuclear oligomerization domain- like receptors. Upon activation, NLRs form multi-subunit protein complexes termed inflammasomes that activate caspase-1 resulting in proteolytic cleavage and maturation of the pro-inflammatory cytokine IL-1. Diverse PAMPs and DAMPs such as lipopolysaccharide, asbestos, ATP, and uric acid lead to NLRP3 activation through increase in ROS. Specifically, pharmacological manipulations resulting in diminished mitochondrial ROS decrease NLRP3 inflammasome activation, but not other inflammasome subsets. Furthermore, pharmacologic or genetic blockade of autophagy, which increases mitochondrial ROS concentrations, enhances inflammasome activation. The release of mitochondrial reactive oxygen species leads to lysosomal membrane permeabilization necessary for proper NLRP3 activation. A consequence of NLRP3 activation is the induction of mitochondrial damage with concomitant block in mitophagy to remove damaged mitochondria. Apart from mitochondrial ROS, release of mitochondrial DNA into the cytosol was found to enhance NLRP3 activation. Later it wa
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