Ratajczak Mariusz Z, Kucia Magda
Stem Cell Institute at Division of Hematology, Department of Medicine and James Graham Brown Cancer Center, University of Louisville, KY, United States.
Center for Preclinical Studies and Technology, Department of Regenerative Medicine Medical University of Warsaw, Warsaw, Poland.
Front Immunol. 2021 Jan 29;11:603942. doi: 10.3389/fimmu.2020.603942. eCollection 2020.
Nlrp3 inflammasome plays a pleiotropic role in hematopoietic cells. On the one hand, physiological activation of this intracellular protein complex is crucial to maintaining normal hematopoiesis and the trafficking of hematopoietic stem progenitor cells (HSPCs). On the other hand, its hyperactivation may lead to cell death by pyroptosis, and prolonged activity is associated with sterile inflammation of the BM and, as a consequence, with the HSPCs aging and origination of myelodysplasia and leukemia. Thus, we need to understand better this protein complex's actions to define the boundaries of its safety window and study the transition from being beneficial to being detrimental. As demonstrated, the Nlrp3 inflammasome is expressed and active both in HSPCs and in the non-hematopoietic cells that are constituents of the bone marrow (BM) microenvironment. Importantly, the Nlrp3 inflammasome responds to mediators of purinergic signaling, and while extracellular adenosine triphosphate (eATP) activates this protein complex, its metabolite extracellular adenosine (eAdo) has the opposite effect. In this review, we will discuss and focus on the physiological consequences of the balance between eATP and eAdo in regulating the trafficking of HSPCs in an Nlrp3 inflammasome-dependent manner, as seen during pharmacological mobilization from BM into peripheral blood (PB) and in the reverse mechanism of homing from PB to BM and engraftment. We propose that both mediators of purinergic signaling and the Nlrp3 inflammasome itself may become important therapeutic targets in optimizing the trafficking of HSPCs in clinical settings.
Nlrp3炎性小体在造血细胞中发挥多效性作用。一方面，这种细胞内蛋白复合物的生理激活对于维持正常造血以及造血干祖细胞（HSPCs）的迁移至关重要。另一方面，其过度激活可能导致细胞焦亡死亡，且持续的活性与骨髓的无菌性炎症相关，进而与HSPCs衰老以及骨髓增生异常综合征和白血病的发生有关。因此，我们需要更好地了解这种蛋白复合物的作用，以界定其安全窗口的界限，并研究从有益到有害的转变。如前所示，Nlrp3炎性小体在HSPCs以及作为骨髓（BM）微环境组成部分的非造血细胞中均有表达且具有活性。重要的是，Nlrp3炎性小体对嘌呤能信号的介质有反应，虽然细胞外三磷酸腺苷（eATP）可激活这种蛋白复合物，但其代谢产物细胞外腺苷（eAdo）则具有相反的作用。在本综述中，我们将讨论并聚焦于eATP和eAdo之间平衡以Nlrp3炎性小体依赖方式调节HSPCs迁移的生理后果，这在从骨髓到外周血（PB）的药理学动员过程中以及从PB归巢到BM并植入的反向机制中都有体现。我们提出，嘌呤能信号的介质以及Nlrp3炎性小体本身都可能成为优化临床环境中HSPCs迁移的重要治疗靶点。
