Mitochondrial Ca2+ and ROS take center stage to orchestrate TNF-α-mediated inflammatory responses

Proinflammatory stimuli induce inflammation that may progress to sepsis or chronic inflammatory disease. The cytokine TNF-alpha is an important endotoxin-induced inflammatory glycoprotein produced predominantly by macrophages and lymphocytes. TNF-alpha plays a major role in initiating signaling pathways and pathophysiological responses after engaging TNF receptors. In this issue of JCI, Rowlands et al. demonstrate that in lung microvessels, soluble TNF-alpha (sTNF-alpha) promotes the shedding of the TNF-alpha receptor 1 ectodomain via increased mitochond.rial Ca2+ that leads to release of mitochondrial ROS. Shedding mediated by TNF-alpha-converting enzyme (TACE) results in an unattached TNF receptor, which participates in the scavenging of sTNF-alpha, thus limiting the propagation of the inflammatory response. These findings suggest that mitochondrial Ca2+, ROS, and TACE might be therapeutically targeted for treating pulmonary endothelial inflammation.