title: Type I NKT-cell-mediated TNF-α is a positive regulator of NLRP3 inflammasome priming.
abstract: The NLRP3 inflammasome plays a crucial role in the innate immune response to pathogens and exogenous or endogenous danger signals. Its activity must be precisely and tightly regulated to generate tailored immune responses. However, the immune cell subsets and cytokines controlling NLRP3 inflammasome activity are still poorly understood. Here, we have shown a link between NKT-cell-mediated TNF-α and NLRP3 inflammasome activity. The NLRP3 inflammasome in APCs was critical to potentiate NKT-cell-mediated immune responses, since C57BL/6 NLRP3 inflammasome-deficient mice exhibited reduced responsiveness to α-galactosylceramide. Importantly, NKT cells were found to act as regulators of NLRP3 inflammasome signaling, as NKT-cell-derived TNF-α was required for optimal IL-1β and IL-18 production by myeloid cells in response to α-galactosylceramide, by acting on the NLRP3 inflammasome priming step. Thus, NKT cells play a role in the positive regulation of NLRP3 inflammasome priming by mediating the production of TNF-α, thus demonstrating another means by which NKT cells control early inflammation.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia; Department of Pathology, University of Melbourne, Parkville, Australia; Immunology in Infection and Cancer Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Melvyn T
authors.initials: MT
authors.lastname: Chow
authors.forename: Helene
authors.initials: H
authors.lastname: Duret
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Christelle
authors.initials: C
authors.lastname: Faveeuw
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Christophe
authors.initials: C
authors.lastname: Paget
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D005699:Galactosylceramides / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D055611:Natural Killer T-Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D005699:Galactosylceramides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide
keywords: Inflammasome; Inflammation; NKT cell; TNF-α