The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis

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 in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β 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-1β cleavage in Pstpip2cmo 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 Pstpip2cmo 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-κB and IL-1β signaling in Pstpip2cmo mice, thereby inducing cmo. These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.

Inflammasomes in Alveolar Bone Loss

“…As stated above, mutated PSTPIP1 in PAPA may increase the activity of the pyrin inflammasome, leading to increased IL-1β expression and aggravated autoinflammation ( 63 ). Bone autoinflammation in mice with CRMO resulting from Pstpip2 gene mutation may be independent of AIM2 but can be protected by deficiencies in NLRP3/caspase-1 and caspase-8 signaling, suggesting that caspase-8 plays a role in IL-1β processing ( 317 , 318 ). Hence, inappropriate inflammasome activation is critical for sterile osteomyelitis induced by gene mutations.…”

The receptor-type protein tyrosine phosphatase CD45 promotes onset and severity of IL-1β–mediated autoinflammatory osteomyelitis

“…Given the dependence of LPS-triggered signaling on MYD88, our data in Figure 1 A make LPS an unlikely candidate for CMO triggering factor in Pstpip2 cmo mice in vivo . On the other hand, published data on the critical importance of spleen tyrosine kinase (SYK) ( 35 ), as well as the data presented in this article, suggest an involvement of an immunoreceptor tyrosine-based activation motif (ITAM)-containing receptor. As a model of these receptors we selected Fc receptors, where the signaling is dependent on the ITAM motif in the receptor gamma chain.…”

“…These observations strongly support the hypothesis that symptom alleviation is caused by reduced activity of SFK. Importantly, Dasari et al recently demonstrated that another protein tyrosine kinase, SYK, is also essential for triggering the disease in Pstpip2 cmo mice (35). Both SFK a SYK are key components of ITAM signaling pathways (40).…”

Role of the F-BAR Family Member PSTPIP2 in Autoinflammatory Diseases

“…The missense mutations in PSTPIP2 leaded to osteomyelitis and osteopathy with bone deformities in mice ( 17 , 23 , 38 ) ( Figure 3 ). As mice cmo disease, which is similar to the experimental model of human CRMO, is specifically mediated by the high production of IL-1β of neutrophils ( 79 ), an autoinflammatory osteomyelitis mediated by caspase-8/NLRP3 inflammasome driven by the nonreceptor tyrosine kinase SYK ( 80 ). IL-1 is a major mediator of innate immunity and is considered a major cytokine in local and systemic inflammation ( 81 ).…”