Inflammasome activation in human and mouse macrophages engulfing autophagic dying cells

Ayna, Gizem

Inflammasome activation in human and mouse macrophages engulfing autophagic dying cells

dc.contributor.advisor	Fésüs, László
dc.contributor.author	Ayna, Gizem
dc.contributor.authorvariant	Ayna, Gizem
dc.contributor.department	Molekuláris sejt- és immunbiológia doktori iskola	hu
dc.contributor.submitterdep	DE--OEC--Általános Orvostudományi Kar --
dc.date.accessioned	2012-07-12T12:40:01Z
dc.date.available	2012-07-12T12:40:01Z
dc.date.created	2012	hu_HU
dc.date.defended	2012-09-21
dc.description.abstract	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.	hu_HU
dc.description.corrector	de
dc.format.extent	89	hu_HU
dc.identifier.uri	http://hdl.handle.net/2437/130985
dc.language.iso	en	hu_HU
dc.subject	Ba/F3	hu_HU
dc.subject	MCF-7
dc.subject	autophagic cell death
dc.subject	phagocytosis
dc.subject	macrophages
dc.subject	NALP-3
dc.subject	inflammasome activation
dc.subject	IL-1β secretion
dc.subject	ATP
dc.subject	P2X7
dc.subject	pannexin-1 channel
dc.subject.discipline	Elméleti orvostudományok	hu
dc.subject.sciencefield	Orvostudományok	hu
dc.title	Inflammasome activation in human and mouse macrophages engulfing autophagic dying cells	hu_HU
dc.title.translated	Inflammasome Activation in Human and Mouse Macrophages Engulfing Autophagic Dying Cells	hu_HU