Spleen tyrosine kinase (SYK) performs a key role upstream of caspase-1 and caspase-8, primarily upregulating NF-κB and IL-1β signaling in Pstpip2cmo mice, and induction of chronic multifocal osteomyelitis (CMO). Here, CASP8 is linked to chronic recurrent multifocal osteomyelitis.