title: Francisella tularensis reveals a disparity between human and mouse NLRP3 inflammasome activation.
abstract: Pathogen-triggered activation of the inflammasome complex leading to caspase-1 activation and IL-1β production involves similar sensor proteins between mouse and human. However, the specific sensors used may differ between infectious agents and host species. In mice, Francisella infection leads to seemingly exclusive activation of the Aim2 inflammasome with no apparent role for Nlrp3. Here we examine the IL-1β response of human cells to Francisella infection. Francisella strains exhibit differences in IL-1β production by influencing induction of IL-1β and ASC transcripts. Unexpectedly, our results demonstrate that Francisella activates the NLRP3 inflammasome in human cells. Francisella infection of THP-1 cells elicits IL-1β production, which is reduced by siRNA targeting of NLRP3. Moreover, in reconstituted 293T cells, Francisella triggers assembly of the NLRP3 inflammasome complex. In addition, inhibitors of reactive oxygen species, cathepsin B, and K(+) efflux pathways, known to specifically influence NLRP3, substantially but not completely impair the Francisella-elicited IL-1β response, suggesting the involvement of another inflammasome pathway. Finally, shRNA targeting of NLRP3 and AIM2 reveals that both pathways contribute to the inflammasome response. Together these results establish NLRP3 as a cytosolic sensor for Francisella in human cells, a role not observed in mouse.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208, USA.
authors.forename: Maninjay K
authors.initials: MK
authors.lastname: Atianand
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Duffy
authors.forename: Aaloki
authors.initials: A
authors.lastname: Shah
authors.forename: Supriya
authors.initials: S
authors.lastname: Kar
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malik
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Harton
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D005604:Francisella tularensis / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D017136:Ion Transport / Q000235:genetics; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013045:Species Specificity; D014406:Tularemia / Q000235:genetics / Q000378:metabolism*
chemical_list: C410167:AIM2 protein, human; C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C533912:CTSB protein, human; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D011188:Potassium