Human Monocytes Engage an Alternative Inflammasome Pathway

Gaidt, Moritz M.; Ebert, Thomas S.; Chauhan, Dhruv; Schmidt, Tobias; Schmid-Burgk, Jonathan L.; Rapino, Francesca, 1982-; Robertson, Avril A. B.; Cooper, Matthew A.; Graf, T. (Thomas); Hornung, Veit

Human Monocytes Engage an Alternative Inflammasome Pathway

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dc.contributor.author Gaidt, Moritz M.ca
dc.contributor.author Ebert, Thomas S.ca
dc.contributor.author Chauhan, Dhruvca
dc.contributor.author Schmidt, Tobiasca
dc.contributor.author Schmid-Burgk, Jonathan L.ca
dc.contributor.author Rapino, Francesca, 1982-ca
dc.contributor.author Robertson, Avril A. B.ca
dc.contributor.author Cooper, Matthew A.ca
dc.contributor.author Graf, T. (Thomas)ca
dc.contributor.author Hornung, Veitca
dc.date.accessioned 2017-05-08T08:38:08Z
dc.date.available 2017-05-08T08:38:08Z
dc.date.issued 2016
dc.description.abstract Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an “alternative inflammasome” that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K+ efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.
dc.description.sponsorship This work was supported by grants from the German Research Foundation (SFB704 and SFB670) to V.H. V.H. is a member of the Excellence cluster ImmunoSensation.
dc.format.mimetype application/pdfca
dc.identifier.citation Gaidt MM, Ebert T, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F et al. Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity. 2016;44(4):833-46. DOI: 10.1016/j.immuni.2016.01.012
dc.identifier.doi http://dx.doi.org/10.1016/j.immuni.2016.01.012
dc.identifier.issn 1074-7613
dc.identifier.uri http://hdl.handle.net/10230/32106
dc.language.iso eng
dc.publisher Elsevierca
dc.relation.ispartof Immunity. 2016;44(4):833-46
dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.immuni.2016.01.012 that appeared in the journal Immunity. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.title Human Monocytes Engage an Alternative Inflammasome Pathwayca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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