Journal article
The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis
The Journal of biological chemistry, Vol.295(11), pp.3394-3400
03/13/2020
DOI: 10.1074/jbc.RA119.010623
PMCID: PMC7076204
PMID: 31719149
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.
Details
- Title: Subtitle
- The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis
- Creators
- Tejasvi K. Dasari - St. Jude Children's Research HospitalRechel Geiger - St. Jude Children's Research HospitalRajendra Karki - St. Jude Children's Research HospitalBalaji Banoth - St. Jude Children's Research HospitalBhesh Raj Sharma - St. Jude Children's Research HospitalPrajwal Gurung - St. Jude Children's Research HospitalAmanda Burton - St. Jude Children's Research HospitalThirumala-Devi Kanneganti - St. Jude Children's Research Hospital
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.295(11), pp.3394-3400
- DOI
- 10.1074/jbc.RA119.010623
- PMID
- 31719149
- PMCID
- PMC7076204
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 7
- Grant note
- American Lebanese Syrian Associated Charities; American Lebanese Syrian Associated Charities (ALSAC) CA163507; AR056296; AI124346; AI101935 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 03/13/2020
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984359862002771
Metrics
8 Record Views