Role of autophagy in myeloid cell differentiation and death

造血干细胞通过分化过程产生人体内所有的血细胞。中性粒细胞是终末分化的髓系细胞的一个例子，是最丰富的白细胞类型，在宿主防御中发挥着关键作用。每天有1000亿个中性粒细胞从骨髓中释放出来，以取代等量的死亡中性粒细胞。因此，中性粒细胞分化、生成或死亡(即细胞凋亡)的不平衡可能导致许多有害的宿主效应。*分化在细胞表型的形成中起关键作用。中性粒细胞线粒体含量有限，线粒体不具有代谢活性，但含有促凋亡蛋白。这种线粒体表型确保了中性粒细胞是短暂的细胞，对凋亡刺激很敏感。尽管这种表型的发育对中性粒细胞的功能至关重要，但在中性粒细胞分化过程中调节线粒体表型发育的途径尚不清楚。*自噬是一种分解代谢过程，它回收或移除细胞内的成分，参与细胞的维持、生存和死亡途径。在红细胞分化过程中，线粒体通过自噬被移除。这对它们的功能至关重要，因为它保护携氧细胞免受线粒体活动引起的氧化损伤。线粒体特异性自噬(即有丝分裂吞噬)是否在中性粒细胞分化中起作用尚不清楚；然而，这似乎有几个原因。首先，中性粒细胞是由与红细胞相同的造血干细胞产生的，因此拥有执行自噬的细胞机制。第二，像红细胞一样，中性粒细胞调节线粒体的含量，这对在终末分化的细胞中产生所需的表型至关重要。因此，我们的研究旨在研究中性粒细胞分化和死亡中有丝分裂的细胞和分子过程以及理解有丝分裂的生理后果。本研究的目的是确定(1)自噬/有丝分裂在中性粒细胞分化过程中线粒体内容和表型变化中的直接细胞和分子作用；(2)分化过程中自噬对中性粒细胞对死亡刺激的反应的影响；以及(3)中性粒细胞分化过程中自噬对死亡刺激后中性粒细胞凋亡的生理影响。总而言之，这项工作将有助于从根本上理解自噬/有丝分裂吞噬在髓系细胞分化和死亡中的重要作用，这可能对理解髓系细胞在衰老、炎症和疾病等众多生物学过程中的活动具有重要意义。

Hematopoietic stem cells generate all the blood cells in the human body through the process of differentiation. Neutrophils, an example of terminally differentiated myeloid cells, are the most abundant type of white blood cell and play a crucial role in host defence. Each day 100 billion neutrophils are released from bone marrow to replace the equivalent number of dying neutrophils. Thus, an imbalance in neutrophil differentiation, generation or death (i.e., apoptosis) can result in numerous detrimental host effects. ******Differentiation plays a key role in developing cellular phenotype. Neutrophils have limited mitochondrial content and possess mitochondria that are not metabolically active but contain pro-apoptotic proteins. This mitochondrial phenotype ensures that neutrophils are short-lived cells, susceptible to apoptotic stimuli. Although the development of this phenotype is critical to neutrophil function, the pathways that regulate the development of mitochondrial phenotype during neutrophil differentiation are unknown. ******Autophagy is a catabolic process that recycles or removes intracellular components and participates in cell maintenance, survival and death pathways. During differentiation of erythrocytes, mitochondria are removed by autophagy. This is critical to their function, as it protects the oxygen carrying cells from oxidative damage caused by mitochondrial activity. Whether mitochondria specific autophagy (i.e. mitophagy) plays a role in neutrophil differentiation is not known; however, it appears likely for several reasons. First, neutrophils are generated from the same hematopoietic stem cell as erythrocytes and thus possess the cellular machinery capable of performing autophagy. Second, like erythrocytes, neutrophils regulate mitochondrial content, which is critical to generating the desired phenotype in the terminally differentiated cell. Therefore, our research aims to study the cell and molecular processes as well as understand the physiological consequences of mitophagy in neutrophil differentiation and death.******The objectives of this proposal are to determine (1) the direct cell and molecular role of autophagy/mitophagy in changes in mitochondrial content and phenotype during neutrophil differentiation; (2) the impact of autophagy during differentiation on the neutrophil's response to a death stimulus; and (3) the physiological impact of autophagy during neutrophil differentiation on neutrophil apoptosis following a death stimulus using transgenic mice with defective autophagy signalling. Collectively, this work will contribute to the fundamental understanding of the essential role of autophagy/mitophagy in myeloid cell differentiation and death, which could have important implications for understanding myeloid cell activity in numerous biological processes such as of aging, inflammation and disease.**