The receptor-type protein tyrosine phosphatase CD45promotes onset and severity of IL-1 beta-mediated autoinflammatory osteomyelitis
Abstract
A number of human autoinflammatory diseases manifest withsevere inflammatory bone destruction. Mouse models of thesediseases represent valuable tools that help us to understand mo-lecular mechanisms triggering this bone autoinflammation.
ThePstpip2cmomouse strain is among the best characterized of these;it harbors a mutation resulting in the loss of adaptor proteinPSTPIP2 and development of autoinflammatory osteomyelitis. InPstpip2cmomice, overproduction of interleukin-1 beta(IL-1 beta)andreactive oxygen species by neutrophil granulocytes leads tospontaneous inflammation of the bones and surrounding softtissues.
However, the upstream signaling events leading to thisoverproduction are poorly characterized. Here, we show thatPstpip2cmomice deficient in major regulator of Src-family kinases(SFKs) receptor-type protein tyrosine phosphatase CD45 displaydelayed onset and lower severity of the disease, while the devel-opment of autoinflammation is not affected by deficiencies inToll-like receptor signaling.
Our data also show deregulation ofpro-IL-1 beta production byPstpip2cmoneutrophils that are attenu-ated by CD45 deficiency. These data suggest a role for SFKs inautoinflammation.
Together with previously published work onthe involvement of protein tyrosine kinase spleen tyrosine kinase,they point to the role of receptors containing immunoreceptortyrosine-based activation motifs, which after phosphorylation bySFKs recruit spleen tyrosine kinase for further signal propagation.We propose that this class of receptors triggers the eventsresulting in increased pro-IL-1 beta synthesis and disease initiationand/or progression.