Szerző szerinti böngészés "Ayna, Gizem"

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    ATP release from dying autophagic cells and their phagocytosis are crucial for inflammasome activation in macrophages
    (2012) Ayna, Gizem; Krysko, Dmitri V.; Kaczmarek, Agnieszka; Petrovski, Goran; Vandenabeele, Peter; Fésüs, László
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    Inflammasome activation in human and mouse macrophages engulfing autophagic dying cells
    Ayna, Gizem; Fésüs, László; Ayna, Gizem; Molekuláris sejt- és immunbiológia doktori iskola; DE--OEC--Általános Orvostudományi Kar --
    Phagocytosis of PAMPs, DAMPs and certain dying cells can activate the inflammasome pathway in macrophages. In our study, we show that both human and mouse macrophages display a pro-inflammatory response to autophagic dying MCF-7 and Ba/F3 cells, but not to living, apoptotic, necrotic or necrostatin-1 treated ones. When we investigated this phenomenon, further it was found that caspase-1 was activated and IL-1β was processed and then secreted in a MyD88-independent manner. Neither caspase-1 inhibited nor caspase-1 deficient macrophages could trigger IL-1β release due to the lack of key component for pro-IL-1β cleavage and maturation before its secretion. Next we clarified which inflammasome is activated by autophagic dying cells and found that NALP-3 deficient macrophages displayed reduced IL-1β secretion, which was also observed in macrophages in which the NALP-3 gene was knocked down. Next, we investigated the upstream mechanism of NALP-3 inflammasome activation triggered by autophagic dying cells. Our results show that during phagocytosis of autophagic dying MCF-7 and Ba/F3 cells exogenous ATP is acting through P2X7 receptor, initiates K+ efflux, inflammasome activation and secretion of IL-1β from human and mouse macrophages. Calreticulin exposure on autophagic dying MCF-7 cells do not play role in inflammasome activation. ATP was secreted from human macrophages during co-incubation with autophagic dying MCF-7 cells which did not release ATP. However, autophagic dying Ba/F3 cells were the source the ATP which activated the P2X7 receptor and lead to inflammasome activation in mouse macrophages. We further showed that pannexin-1 channel is responsible for ATP secretion from autophagic dying Ba/F3 cells. MCF-7 and Ba/F3 cells dying with involvement of autophagy were capable of preventing crude LPS-induced pro-inflammatory cytokine release but pro-inflammatory cytokines were produced and secreted from human macrophages triggered by autophagic dying cells as a result of the secreted IL-1β. Finally, it was observed that injection of autophagic dying cells intraperitoneally induced an acute inflammatory reaction by recruiting neutrophils and monocytes/macrophages.