NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

Prajwal Gurung; Amanda Burton; Thirumala-Devi Kanneganti

doi:10.1073/pnas.1601636113

Back

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

Journal article

Open access

Peer reviewed

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

Prajwal Gurung, Amanda Burton and Thirumala-Devi Kanneganti

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

Files and links (1)

url

https://doi.org/10.1073/pnas.1601636113View

Published (Version of record) Open Access

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 in Pstpip2cmo mice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease in Pstpip2cmo mice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 in Pstpip2cmo mice provides similar protection as observed in caspase-1 and caspase-8–deficient Pstpip2cmo mice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease in Pstpip2cmo mice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseased Ptpn6spin 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 in Pstpip2cmo mice.

Inflammasomes - metabolism

Cytoskeletal Proteins - genetics

NLR Family, Pyrin Domain-Containing 3 Protein

Osteomyelitis - genetics

Caspase 8 - metabolism

Caspase 1 - metabolism

Interleukin-1beta - genetics

Osteomyelitis - metabolism

Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics

Inflammasomes - genetics

Mice, Knockout

Caspase 8 - genetics

Carrier Proteins - genetics

Animals

Carrier Proteins - metabolism

Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism

Caspase 1 - genetics

Interleukin-1beta - metabolism

Osteomyelitis - pathology

Adaptor Proteins, Signal Transducing - genetics

Cytoskeletal Proteins - metabolism

Mice

Adaptor Proteins, Signal Transducing - metabolism

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 38105
Amanda Burton - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
Thirumala-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
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
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

22 Record Views

116 Times Cited - Web of Science