| First Author | Dasari TK | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 11 | Pages | 3394-3400 |
| PubMed ID | 31719149 | Mgi Jnum | J:286548 |
| Mgi Id | MGI:6401271 | Doi | 10.1074/jbc.RA119.010623 |
| Citation | Dasari TK, et al. (2020) The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis. J Biol Chem 295(11):3394-3400 |
| abstractText | 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-1beta and not by IL-1alpha, delineating the molecular pathways contributing to pathogenic IL-1beta 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-1beta 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-kappaB and IL-1beta signaling in Pstpip2(cmo) mice, thereby inducing cmo These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO. |
