Role of autophagy in myeloid cell differentiation and death

造血干细胞通过分化过程产生人体所有的血细胞。中性粒细胞是终末分化骨髓细胞的一个例子，是白细胞中数量最多的一种，在宿主防御中起着至关重要的作用。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）的不平衡可导致许多有害的宿主效应。

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.