Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

Chronic recurrent multifocal osteomyelitis (CRMO) is a human auto-inflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL- 1RI in cmomice resulted in a significant reduction in the time to onset of disease aswell as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1 beta, but not IL- 1a, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide- binding domain, leucine- rich repeat- containing family, pyrin domain- containing 3 (NLRP3) inflammasome as well as caspase- 1. Neutrophils, but not bone marrow- derived macrophages, from cmo mice secreted increased IL-1 beta in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome- independent role for IL-1 beta in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1 beta as a therapeutic strategy in CRMO.