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

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-1 beta but not IL-1 alpha. The precise molecular pathways that promote pathogenic IL-1 beta production in Pstpip2(cmo) mice remain unidentified. Furthermore, how IL-1 beta provokes inflammatory bone disease in Pstpip2(cmo) mice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 in Pstpip2(cmo) mice provides similar protection as observed in caspase-1 and caspase-8-deficient Pstpip2(cmo) mice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease in Pstpip2(cmo) mice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseased Ptpn6spin neutrophils. Data from our chimera studies demonstrated that IL-1 beta produced by hematopoietic cells is sensed by the radioresistant compartment to promote bone disease. Furthermore, our results showed that the IL-1 beta signaling is unidirectional and feedback signaling of IL-1 beta 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-1 beta maturation and the directionality of IL-1 beta in driving disease in Pstpip2(cmo) mice.