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.
Highlights
Cytokine-driven inflammation is a critical component of the immune system’s defense mechanisms
It can be likely explained by its involvement in IL-1 receptor signaling, which is required for the disease development in Pstpip2cmo mice
Pstpip2cmo/ TrifLps2/Lps2 mice developed the chronic multifocal osteomyelitis (CMO) disease with identical kinetics as Pstpip2cmo mice (Fig. 1B). These data suggest that priming of leukocytes through TLR/MyD88 or TLR/TRIF signaling does not play any major role in CMO development since Pstpip2cmo hematopoietic cells without functional MyD88 or TRIF adaptors were fully capable of driving the autoinflammation
Summary
Cytokine-driven inflammation is a critical component of the immune system’s defense mechanisms. Increased production of active IL-1β was observed in affected tissues and in Pstpip2cmo neutrophils [6,7,8, 10], a cell type critical for triggering this disease [7, 9].
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