The nonreceptor tyrosine kinase SYK induces autoinflammatory osteomyelitis in a mouse model of chronic recurrent multifocal osteomyelitis

Abstract

Abstract Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2cmo mice, which carry a missense mutation in the proline-serine-threonine phosphatase-interacting protein 2(Pstpip2) gene. As cmo disease is mediated specifically by IL-1β, not IL-1α, delineating the molecular pathways contributing to the pathogenic IL-1β production is crucial to develop targeted therapies. In particular, our earlier findings support redundant roles for NLRP3 and caspase-1 with caspase-8 in instigating the disease. However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in Pstpip2cmo mice are not well understood. Therefore, we investigated the signaling pathways in these mice and characterized the central role of the nonreceptor tyrosine kinase SYK in mediating osteomyelitis. We demonstrate that while absent in melanoma 2 (AIM2), receptor-interacting serine/threonine protein kinase 3 (RIPK3), and caspase recruitment domain-containing protein 9 (CARD9) are dispensable for osteomyelitis induction in Pstpip2cmo mice, genetic deletion of Syk completely rescues disease. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally regulates NF-κB and IL-1β signaling in Pstpip2cmo mice to instigate disease. These data provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.