Journal Article

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

Kanneganti, Thirumala-Devi, Burton, Amanda, Gurung, Prajwal

2016

Overview

Missense mutation in the proline-serine-threonine phosphataseinteracting 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.

• Publisher: National Academy of Sciences
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animals / Biological Sciences / Carrier Proteins - genetics / Carrier Proteins - metabolism / Caspase 1 - genetics / Caspase 1 - metabolism / Caspase 8 - genetics / Caspase 8 - metabolism / Cytoskeletal Proteins - genetics / Cytoskeletal Proteins - metabolism / Immunology and Inflammation / Inflammasomes - genetics / Inflammasomes - metabolism / Interleukin-1beta - genetics / Interleukin-1beta - metabolism / Mice / Mice, Knockout / NLR Family, Pyrin Domain-Containing 3 Protein / Osteomyelitis - genetics / Osteomyelitis - metabolism / Osteomyelitis - pathology / Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism