Journal article
NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β-mediated osteomyelitis
Proceedings of the National Academy of Sciences - PNAS, Vol.113(16), pp.4452-4457
04/19/2016
DOI: 10.1073/pnas.1601636113
PMCID: PMC4843439
PMID: 27071119
Abstract
Missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene results in the development of spontaneous chronic bone disease characterized by bone deformity and inflammation that is reminiscent of patients with chronic multifocal osteomyelitis (cmo). Interestingly, this disease is specifically mediated by IL-1β but not IL-1α. The precise molecular pathways that promote pathogenic IL-1β production inPstpip2(cmo)mice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease inPstpip2(cmo)mice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 inPstpip2(cmo)mice provides similar protection as observed in caspase-1 and caspase-8-deficientPstpip2(cmo)mice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease inPstpip2(cmo)mice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseasedPtpn6(spin)neutrophils. Data from our chimera studies demonstrated that IL-1β produced by hematopoietic cells is sensed by the radioresistant compartment to promote bone disease. Furthermore, our results showed that the IL-1β signaling is unidirectional and feedback signaling of IL-1β onto the hematopoietic compartment is not important for disease induction. In conclusion, our studies have uncovered the combined actions of the NLRP3 inflammasome and caspase 8 leading to IL-1β maturation and the directionality of IL-1β in driving disease inPstpip2(cmo)mice.
Details
- Title: Subtitle
- NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β-mediated osteomyelitis
- Creators
- Prajwal Gurung - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105Amanda Burton - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105Thirumala-Devi Kanneganti - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 thirumala-devi.kanneganti@stjude.org
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.113(16), pp.4452-4457
- DOI
- 10.1073/pnas.1601636113
- PMID
- 27071119
- PMCID
- PMC4843439
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- R01 AI101935 / NIAID NIH HHS R01 CA163507 / NCI NIH HHS R01 AI124346 / NIAID NIH HHS P30 CA021765 / NCI NIH HHS R01 AR056296 / NIAMS NIH HHS AI101935 / NIAID NIH HHS CA163507 / NCI NIH HHS AR056296 / NIAMS NIH HHS
- Language
- English
- Date published
- 04/19/2016
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094613202771
Metrics
19 Record Views