Cyclophilin D disruption attenuates lipopolysaccharide-induced inflammatory response in primary mouse macrophages.
According to recent results, various mitochondrial processes can actively regulate the immune response. In the present report, we studied whether mitochondrial permeability transition (mPT) has such a role. To this end, we compared bacterial lipopolysaccharide (LPS)-induced inflammatory response in cyclophilin D (CypD) knock-out and wild-type mouse resident peritoneal macrophages. CypD is a regulator of mPT; therefore, mPT is damaged in CypD(-/-) cells. We chose this genetic modification-based model because the mPT inhibitor cyclosporine A regulates inflammatory processes by several pathways unrelated to the mitochondria. The LPS increased mitochondrial depolarisation, cellular and mitochondrial reactive oxygen species production, nuclear factor-κB activation, and nitrite- and tumour necrosis factor α accumulation in wild-type cells, but these changes were diminished or absent in the CypD-deficient macrophages. Additionally, LPS enhanced Akt phosphorylation/activation as well as FOXO1 and FOXO3a phosphorylation/inactivation both in wild-type and CypD(-/-) cells. However, Akt and FOXO phosphorylation was significantly more pronounced in CypD-deficient compared to wild-type macrophages. These results provide the first pieces of experimental evidence for the functional regulatory role of mPT in the LPS-induced early inflammatory response of macrophages.
Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 12 Szigeti St., H-7624 Pecs, Hungary.
Janos
J
Priber
Fruzsina
F
Fonai
Peter Balazs
PB
Jakus
Boglarka
B
Racz
Christos
C
Chinopoulos
Laszlo
L
Tretter
Ferenc
F
Gallyas
Balazs
B
Sumegi
Balazs
B
Veres
D000818:Animals; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000081406:Peptidyl-Prolyl Isomerase F; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D008070:Lipopolysaccharides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D021983:Cyclophilins
Cyclophilin D disruption; espèces réactives d’oxygène; facteur de transcription nucléaire NF-kB; macrophages péritonéaux; mitochondrial permeability transition; nuclear factor-κB; peritoneal macrophages; reactive oxygen species; rupture du gène de la cyclophilline D; transition de perméabilité mitochondriale