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The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis
Cited 13 time in
Web of Science
Cited 14 time in Scopus
- Authors
- Issue Date
- 2020-03
- Citation
- Journal of Biological Chemistry, Vol.295 No.11, pp.3394-3400
- 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.
- ISSN
- 0021-9258
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