We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1β signaling in <i>Pstpip2<sup>cmo</sup></i> mice and thereby induces <i>cmo.</i> These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.