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.

中文翻译：

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受体型蛋白酪氨酸磷酸酶 CD45 促进 IL-1β 介导的自身炎症性骨髓炎的发作和严重程度。

许多人类自身炎症性疾病表现为严重的炎症性骨破坏。这些疾病的小鼠模型代表了有价值的工具，可以帮助我们了解触发这种骨骼自身炎症的分子机制。Pstpip2cmo 小鼠品系是其中特征最好的品系之一。它含有导致接头蛋白 PSTPIP2 丢失和自身炎症性骨髓炎发展的突变。在 Pstpip2cmo 小鼠中，中性粒细胞过度产生白细胞介素-1β (IL-1β) 和活性氧会导致骨骼和周围软组织的自发性炎症。然而，导致这种生产过剩的上游信号事件的特征很差。这里，我们表明，缺乏 Src 家族激酶 (SFKs) 受体型蛋白酪氨酸磷酸酶 CD45 的主要调节因子的 Pstpip2cmo 小鼠表现出疾病的延迟发作和较低的严重程度，而自身炎症的发展不受 Toll 样受体信号传导缺陷的影响. 我们的数据还显示 Pstpip2cmo 中性粒细胞对 pro-IL-1β 产生的失调，这些中性粒细胞因 CD45 缺乏而减弱。这些数据表明 SFK 在自身炎症中的作用。连同先前发表的关于蛋白质酪氨酸激酶脾酪氨酸激酶参与的工作，他们指出了含有免疫受体酪氨酸激活基序的受体的作用，这些基序在被 SFK 磷酸化后募集脾酪氨酸激酶用于进一步的信号传播。