Critical role for inflammasome-independent IL-1β production in osteomyelitis

Abstract

The immune system plays an important role in the pathophysiology of many acute and chronic bone disorders, but the specific inflammatory networks that regulate individual bone disorders remain to be elucidated. Here, we characterized the osteoimmunological underpinnings of osteolytic bone disease in Pstpip2 cmo mice. These mice carry a homozygous L98P missense mutation in the Pombe Cdc15 homology family phosphatase PSTPIP2 that is responsible for the development of a persistent autoinflammatory disease resembling chronic recurrent multifocal osteomyelitis in humans. We found that improper regulation of IL-1β production resulted in secondary induction of inflammatory cytokines, inflammatory cell infiltration in the bone, and unremitting bone inflammation. Aberrant Il1β expression precedes the development of osteolytic damage in young Pstpip2 cmo mice, and genetic deletion of Il1r and Il1β, but not Il1α, rescued osteolytic bone disease in mutant mice. Intriguingly, caspase-1 and nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 activation in the inflammasome complex were dispensable for Pstpip2 cmo -mediated bone disease. Thus, our findings establish a critical role for inflammasome-independent production of IL-1β in osteolytic bone disease and identify PSTPIP2 as a negative regulator of caspase-1-autonomous IL-1β production.osteoimmunology | interleukin-1 | autoinflammation

PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk

“…Because recent reports showed that IL-1b and inflammasomeactivated caspases are critical for the disease development in CMO mice (35)(36)(37), we decided to analyze the silica-triggered IL-1b production in more detail, especially with respect to the interactions among PSTPIP2, SHIP1, and Csk described earlier. To address the question of PSTPIP2 phosphorylation under these conditions, we performed the immunoprecipitation of endogenous PSTPIP2 from unstimulated or LPS-primed and silica-stimulated BM cells.…”

“…In addition, more recent work has suggested that neutrophils may also be a critical cell type in disease initiation (35,36). Similar to several other autoinflammatory syndromes, the disease appears to be, at least in part, caused by the enhanced production of IL-1b (35,37). The molecular mechanism of how PSTPIP2 prevents autoinflammatory disease development remains largely unknown.…”

IL-1β and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1α or Caspase-8 in a Mouse Model of Familial Mediterranean Fever

“…5 Both IL-1a and IL-1b are capable of instigating sterile inflammation and we previously have shown that these cytokines drive distinct neutrophilmediated autoinflammatory disorders. 10,34 Although a reason for this specificity currently is unknown, a possible reason could be the nature of cell death perturbed in each autoinflammatory disorder. 9 Although necrotic cell death releases bioactive IL-1a, IL-1b requires caspase-1e and/or caspase-8emediated maturation and release.…”

Inflammatory osteolysis: a conspiracy against bone

“…Mice harboring a spontaneous missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene, which abolishes protein expression, develop a phenotype reminiscent of CRMO, with enhanced osteoclastogenesis and bone resorption (137). These mutant mice overproduce IL-1β due to combined and redundant actions of the NLRP3 inflammasome and caspase 8 (138)(139)(140), suggesting that inflammasome-independent IL-1β release may occur in some situations.…”