title: Mitochondrial Ca²+ and ROS take center stage to orchestrate TNF-α-mediated inflammatory responses.
abstract: Proinflammatory stimuli induce inflammation that may progress to sepsis or chronic inflammatory disease. The cytokine TNF-α is an important endotoxin-induced inflammatory glycoprotein produced predominantly by macrophages and lymphocytes. TNF-α 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-α (sTNF-α) promotes the shedding of the TNF-α receptor 1 ectodomain via increased mitochondrial Ca²+ that leads to release of mitochondrial ROS. Shedding mediated by TNF-α-converting enzyme (TACE) results in an unattached TNF receptor, which participates in the scavenging of sTNF-α, 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Dada
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D004731:Endotoxins / Q000378:metabolism; D007249:Inflammation; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D002118:Calcium