![Figure 7. Extracellular mitochondria and sPLA2-IIA amplify inflammation in vivo. (A) Intravenous injection of mitochondrial hydrolytic products (sPLA2-IIA–treated mitochondria, black triangle) in sPLA2-IIA–deficient mice significant lowers body temperature (Δ temperature vs PBS-injected mice of respective background) after 4 hours (n = 6/group; data are mean ± SEM, **P < .005 compared with sPLA2-IIA–untreated mitochondria [▪] or sPLA2-IIA alone [●]). Intravenous injection of mitochondria (sPLA2-IIA untreated, ☐) in sPLA2-IIA–sufficient mice significantly lowers body temperature after 24 hours. Only a modest temperature decrease was observed in sPLA2-IIA–untreated mitochondria (▪) in sPLA2-IIA–deficient mice (n ≥ 3/group; data are mean ± SEM, **P < .005). (B) sPLA2-IIA–generated mitochondrial products trigger inflammation in vivo. Mitochondria incubated in the presence of recombinant sPLA2-IIA and injected into the air pouch of C57BL/6N mice induce the production of (left) IL-1β and (right) IL-6. Diluent (PBS), sPLA2-IIA alone, or untreated mitochondria induce modest cytokine production when injected separately (n = 7; data are mean ± SEM, **P < .005 compared with mitochondria incubated in the absence of sPLA2-IIA). (C) Mitochondria accumulation in the liver induces numerous proinflammatory genes that are amplified in the presence of endogenous sPLA2-IIA. mRNA expression of inflammatory genes relevant to neutrophil function was quantified in the liver of sPLA2-IIA–sufficient and –deficient mice intravenously injected with mitochondria (n = 3 per group; data expressed as the ratio of specific mRNA expression ratio (sPLA2-IIA sufficient/deficient mice). (D) Schematic representation of the mechanism of action of extracellular mitochondria and sPLA2-IIA in sterile inflammatory conditions. On activation, platelets release MPs, mitoMPs, and freeMitos. Mitochondrial membrane phospholipids may be hydrolyzed by sPLA2-IIA, generating bioactive mediators (fatty acids, lysophospholipids, and mtDNA) and promoting neutrophil proinflammatory responses.](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/124/14/10.1182_blood-2014-05-573543/4/2173f7.jpeg?Expires=1723199189&Signature=AdONz0zucOKGVgmMxvudT~tbjbwY86tdmJsD3~skv8GXFpKvt~A9etLbQS9-r2COQ0vPtz654dnqwJKwsMeahw9nyu5RW5LS-ar0jLsvjow0udLFjgN9cjhtqk907Xqezi264fY052Jeh1AGoEjyMOhGnmpf5KofZiy~~PiQ4q1-ZrWB60aXmH-pLOrgILaUs599g251CaybJ6tm8A9zf8ZIfnVzfixjv7UPtj4FnSkbxdUdLdFG4xPTHErCF7ax7qi-daIst~k7agV361Y8Aa2lS7xnnkzzlyh4DvK9JF~6FqXLSCDV4IXFX21BK8zWSCSrHedNuRVrgtcv14SgRw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Extracellular mitochondria and sPLA2-IIA amplify inflammation in vivo. (A) Intravenous injection of mitochondrial hydrolytic products (sPLA2-IIA–treated mitochondria, black triangle) in sPLA2-IIA–deficient mice significant lowers body temperature (Δ temperature vs PBS-injected mice of respective background) after 4 hours (n = 6/group; data are mean ± SEM, **P < .005 compared with sPLA2-IIA–untreated mitochondria [▪] or sPLA2-IIA alone [●]). Intravenous injection of mitochondria (sPLA2-IIA untreated, ☐) in sPLA2-IIA–sufficient mice significantly lowers body temperature after 24 hours. Only a modest temperature decrease was observed in sPLA2-IIA–untreated mitochondria (▪) in sPLA2-IIA–deficient mice (n ≥ 3/group; data are mean ± SEM, **P < .005). (B) sPLA2-IIA–generated mitochondrial products trigger inflammation in vivo. Mitochondria incubated in the presence of recombinant sPLA2-IIA and injected into the air pouch of C57BL/6N mice induce the production of (left) IL-1β and (right) IL-6. Diluent (PBS), sPLA2-IIA alone, or untreated mitochondria induce modest cytokine production when injected separately (n = 7; data are mean ± SEM, **P < .005 compared with mitochondria incubated in the absence of sPLA2-IIA). (C) Mitochondria accumulation in the liver induces numerous proinflammatory genes that are amplified in the presence of endogenous sPLA2-IIA. mRNA expression of inflammatory genes relevant to neutrophil function was quantified in the liver of sPLA2-IIA–sufficient and –deficient mice intravenously injected with mitochondria (n = 3 per group; data expressed as the ratio of specific mRNA expression ratio (sPLA2-IIA sufficient/deficient mice). (D) Schematic representation of the mechanism of action of extracellular mitochondria and sPLA2-IIA in sterile inflammatory conditions. On activation, platelets release MPs, mitoMPs, and freeMitos. Mitochondrial membrane phospholipids may be hydrolyzed by sPLA2-IIA, generating bioactive mediators (fatty acids, lysophospholipids, and mtDNA) and promoting neutrophil proinflammatory responses.
