ABSTRACT
Mitochondria react to infection with sub-lethal signals in the apoptosis pathway. Mitochondrial signals can be inflammatory but mechanisms are only partially understood. We show that activation of the caspase-activated DNase (CAD) mediates mitochondrial pro-inflammatory functions and substantially contributes to host defense against viral infection. In cells lacking CAD, the pro-inflammatory activity of sub-lethal signals was reduced. Experimental activation of CAD caused transient DNA-damage and a pronounced DNA damage response, involving major kinase signaling pathways, NF-κB and cGAS/STING, driving the production of interferon, cytokines/chemokines and attracting neutrophils. The transcriptional response to CAD-activation was reminiscent of the reaction to microbial infection. CAD-deficient cells had a diminished response to viral infection. Influenza virus infected CAD-deficient mice displayed reduced inflammation in lung tissue, higher viral titers and increased weight loss. Thus, CAD links the mitochondrial apoptosis system and cell death caspases to host defense. CAD-driven DNA damage is a physiological element of the inflammatory response to infection.
Subject(s)
DNA Damage , Inflammation , Mitochondria , Animals , Inflammation/pathology , Inflammation/metabolism , Mice , Mitochondria/metabolism , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/metabolism , Mice, Inbred C57BL , Apoptosis , Humans , NF-kappa B/metabolism , Deoxyribonucleases/metabolism , Deoxyribonucleases/genetics , Mice, Knockout , Signal Transduction , Endodeoxyribonucleases/metabolism , Endodeoxyribonucleases/genetics , Endodeoxyribonucleases/deficiency , NucleotidyltransferasesABSTRACT
Complete disruption of an expanded polytetrafluoroethylene (ePTFE) vascular graft is rare. This is a report of a case of a 70 year old man presenting with left shoulder dislocation, which was reduced immediately. Two weeks later, the patient presented with Rutherford 2b bilateral lower limb ischaemia related to the thrombosis of an ePTFE axillobifemoral bypass. The graft was implanted five years earlier for treatment of an aorto-enteric fistula secondary to an infected aortobifemoral bypass. A non-anastomotic pseudoaneurysm associated with complete disruption of the ePTFE graft was found. Systematic analysis of the explant showed that the rupture occurred at the level of a ringed external support and that ongoing tears also occurred on the posterior wall of the graft at the level of this external support. In conclusion, complete analysis of failure mechanisms even from an isolated report is mandatory.
