The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis.

ABSTRACT: Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2^cmo mice, which carry a missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene. As cmo disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1? and not by IL-1?, delineating the molecular pathways contributing to pathogenic IL-1? production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating cmo However, the signaling components upstream of caspase-8 and pro-IL-1? cleavage in Pstpip2^cmo mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain-containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in Pstpip2^cmo mice, whereas genetic deletion of Syk completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-?B and IL-1? signaling in Pstpip2^cmo mice, thereby inducing cmo These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.

SUBMITTER: Dasari TK 

PROVIDER: S-EPMC7076204 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature