未经证实:自身炎性疾病的特征是先天免疫系统失调,导致自发性无菌炎症。该组疾病的公认动物模型之一是小鼠品系Pstpip2cmo。在这种菌株中,接头蛋白PSTPIP2的缺失导致自身炎性疾病慢性多灶性骨髓炎。它表现为后肢和尾巴的骨骼和周围软组织的无菌炎症。中性粒细胞产生IL-1β和活性氧的增加推动了疾病的发展。然而,连接PSTPIP2和这些途径的分子机制尚未建立。可能参与这些机制的候选蛋白包括PSTPIP2结合配偶体,PEST家族磷酸酶(PEST-PTP)和磷酸肌醇磷酸酶SHIP1。
未经批准:为了解决这些蛋白质在PSTPIP2介导的炎症控制中的作用,我们已经产生了小鼠品系,其中PSTPIP2中的PEST-PTP或SHIP1结合位点已被破坏。在这些老鼠品系中,我们跟踪疾病症状和各种炎症标志物。
未经证实:我们的数据显示PEST-PTP结合位点的突变会导致症状性疾病,而缺乏SHIP1相互作用位点的小鼠仍然无症状。重要的是,PSTPIP2的两个结合配偶体对IL-1β产生的控制同样有贡献,而PEST-PTP在活性氧的调节中起主导作用。此外,PEST-PTP与PSTPIP2的相互作用调节中性粒细胞产生趋化因子CXCL2。它的分泌可能会产生一个正反馈回路,驱动中性粒细胞募集到受影响的组织。
未经批准:我们证明了PSTPIP2结合的PEST-PTPs和SHIP1共同控制IL-1β途径。此外,PEST-PTP在控制活性氧和趋化因子的产生方面具有独特的作用,在没有PEST-PTP与PSTPIP2结合的情况下,将平衡转向有症状的疾病。
Autoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2cmo . In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1β and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1.
To address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers.
Our data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1β production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues.
We demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease.