title: NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β-mediated osteomyelitis.
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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Amanda
authors.initials: A
authors.lastname: Burton
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 thirumala-devi.kanneganti@stjude.org.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010019:Osteomyelitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C486383:Pstpip2 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020170:Caspase 1
keywords: NLRP3; PSTPIP2; caspase 1; caspase 8; inflammasome