The receptor-type protein tyrosine phosphatase CD45 promotes onset and severity of IL-1β–mediated autoinflammatory osteomyelitis |
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Authors: | Jarmila Kralova Nataliia Pavliuchenko Matej Fabisik Kristyna Ilievova Frantisek Spoutil Jan Prochazka Jana Pokorna Radislav Sedlacek Tomas Brdicka |
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Institution: | 1.Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic;2.Charles University, Faculty of Science, Prague, Czech Republic;3.Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic;4.Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic |
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Abstract: | A number of human autoinflammatory diseases manifest with severe inflammatory bone destruction. Mouse models of these diseases represent valuable tools that help us to understand molecular mechanisms triggering this bone autoinflammation. The Pstpip2cmo mouse strain is among the best characterized of these; it harbors a mutation resulting in the loss of adaptor protein PSTPIP2 and development of autoinflammatory osteomyelitis. In Pstpip2cmo mice, overproduction of interleukin-1β (IL-1β) and reactive oxygen species by neutrophil granulocytes leads to spontaneous inflammation of the bones and surrounding soft tissues. However, the upstream signaling events leading to this overproduction are poorly characterized. Here, we show that Pstpip2cmo mice deficient in major regulator of Src-family kinases (SFKs) receptor-type protein tyrosine phosphatase CD45 display delayed onset and lower severity of the disease, while the development of autoinflammation is not affected by deficiencies in Toll-like receptor signaling. Our data also show deregulation of pro-IL-1β production by Pstpip2cmo neutrophils that are attenuated by CD45 deficiency. These data suggest a role for SFKs in autoinflammation. Together with previously published work on the involvement of protein tyrosine kinase spleen tyrosine kinase, they point to the role of receptors containing immunoreceptor tyrosine-based activation motifs, which after phosphorylation by SFKs recruit spleen tyrosine kinase for further signal propagation. We propose that this class of receptors triggers the events resulting in increased pro-IL-1β synthesis and disease initiation and/or progression. |
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Keywords: | CD45 PTPRC PSTPIP2 autoinflammation chronic recurrent multifocal osteomyelitis |
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