垂死细胞的吞噬细胞清除及其意义。

IF 7.5 2区 医学 Q1 IMMUNOLOGY
Kodi S. Ravichandran
{"title":"垂死细胞的吞噬细胞清除及其意义。","authors":"Kodi S. Ravichandran","doi":"10.1111/imr.13285","DOIUrl":null,"url":null,"abstract":"<p>It is estimated that an average adult human turns over roughly 330 ± 20 billion cells every day as part of healthy living.<span><sup>1, 2</sup></span> This translates to 0.4% of our body mass. Such a large number for cell turnover then begs the question—what are these cells and why? The reasons for this are multi-factorial. First, there are cells in the body that have a finite life span, such as neutrophils (~1 day) and erythrocytes (~120 days), and there are also other cell types such as many hematopoietic cells that have a life span of a few days to few weeks; these need to be removed after their useful life span and replaced by new cells. Second, there are many aspects of development where we generate excess cells, of which only a few are deemed fit to progress to full maturation, and the rest undergo death and need to be removed; examples of this include development of T cells in the thymus, B cells in the bone marrow, and also adult neurogenesis in the brain.<span><sup>1</sup></span> Third, there are also “damaged” cells that emerge daily in the body, such as due to light/UV damage, for example skin and photoreceptors of the eye.<span><sup>3</sup></span> Thus, all these turnover events result in a large number of cells undergoing death essentially in all organs and tissues, albeit at different magnitude.<span><sup>2</sup></span> Although there are many different forms of death processes, the cells that are destined die via homeostatic turnover do so primarily via the process of caspase-dependent apoptosis.<span><sup>4</sup></span></p><p>What happens to these dying cells? Despite the billions of dying cells per day, when one looks at tissues, it is hard to recognize dying cells, even in those with high cellular turnover. This is because the recognition and clearance of dying cells is remarkably efficient.<span><sup>5, 6</sup></span> Just like there is a dedicated set of molecules and mechanisms to induce programmed cell death, we also possess a dedicated machinery to recognize and remove these dying cells.<span><sup>7</sup></span> Such clearance under homeostasis conditions occurs quickly, efficiently, and from an immunological perspective, quietly.<span><sup>8</sup></span> It is worth noting that just like the apoptotic cell death machinery, the clearance processes are also highly conserved evolutionarily, and studies from the nematode, flies, zebrafish, mice, and humans have established the conserved components of the clearance process.<span><sup>9, 10</sup></span> This volume of Immunological Reviews focuses on different aspects of the cell clearance process and its implications to homeostasis and disease.</p><p>While there are different forms of phagocytosis, the recognition and clearance of apoptotic cells by phagocytes has been termed “efferocytosis,” a term originally coined by Dr. Peter Henson. (where “effero” means “carry to the grave”).<span><sup>11</sup></span> This should be distinguished from Fc receptor mediated phagocytosis or complement receptor-mediated phagocytosis, which involves opsonization of target cells by specific ligands and uptake via the respective receptors. A key distinction from the other forms of phagocytosis is that the apoptotic cell clearance does not induce an immune response; further efferocytosis is also actively anti-inflammatory.<span><sup>8</sup></span> This makes sense when one considers the fact that if we were to induce an inflammatory response to billions of cells that we clear every day, we may all end up as walking bags of inflammation. However, the failure to clear the apoptotic cells promptly can induce secondary necrosis that can lead to inflammatory sequelae, as detailed by some of the chapters in this volume.</p><p>Works from a number of laboratories have now established that there are different steps to recognition and removal of dying cells.<span><sup>1, 12</sup></span> The first step is the recognition of the dying cells. When phagocytes such as macrophages, dendritic cells, or healthy neighbors are in close proximity to the dying cell, specific molecules on the apoptotic cells are recognized by specific receptors on the engulfing cell leading to subsequent intracellular signaling, cytoskeletal reorganization, and corpse internalization.<span><sup>13</sup></span> While there are many ligands exposed on cells undergoing apoptosis, the best detailed is the exposure of the phospholipid phosphatidylserine (PtdSer).<span><sup>14, 15</sup></span> PtdSer is normally kept via an active and energy dependent process on the inner leaflet but gets exposed on the outer leaflet as part of the apoptotic process.<span><sup>15, 16</sup></span> This PtdSer in turn, gets recognized by multiple PtdSer recognition receptors—either directly, or indirectly, via intermediary bridging molecules.<span><sup>16, 17</sup></span> As part of the first chapter, Dr. Tal Brustyn-Cohen details one of the best described receptor families linked to clearance of apoptotic cells, namely the TAM receptors.<span><sup>18</sup></span> These TAM receptors recognize PtdSer indirectly via Gas6 or Protein S that bind PtdSer, and this chapter details the role of TAM receptors in different contexts and highlights their role in other physiology.</p><p>One of the challenges in studying cell clearance in the mammals is that multiple homologues for engulfment receptors and signaling molecules, and the complexities that arise when individual knockouts do not often have a clear phenotype. Thus, defining the function of individual molecules, as well as visualizing cell death and clearance in vivo have been a challenge for the past couple of decades. Will Wood, Andrew Davidson, and colleagues detail the beautiful model systems for cell death and efferocytosis in the fruit fly Drosophila that have provided many new insights.<span><sup>19</sup></span> They also detail new approaches that have been developed to visualize apoptosis and efferocytosis in vivo, plus the different molecular mechanisms of clearance employed by Drosophila macrophages to clear dying cells.</p><p>After a phagocyte engulfs an apoptotic cell, a second challenge ensues—that is, digesting the corpse. This is no small feat, as this involves digesting another cell that is often nearly the same size as the phagocyte itself. Further, many phagocytes engulf multiple apoptotic cells.<span><sup>20</sup></span> Mylvaganam and Freeman take a comprehensive approach to how a phagocyte resolves a phagolysosome as well as aspects of the membrane traffic, and the role of solute carriers in managing some of the contents of the corpse. They also put this in disease contexts with lysosomal storage disorders.<span><sup>21</sup></span></p><p>Another inherent challenge that the phagocyte faces is how to handle all the excess biomass. To put it another way, when a phagocyte engulfs an apoptotic cell, it basically doubles its lipids, carbohydrates, and proteins, to name a few of the corpse contents. Further, phagocytes such as macrophages ingest multiple corpses in succession, leading to even greater challenge of dealing with all this excess metabolic overload.<span><sup>20, 22</sup></span> Shilperoort, Tabas, and colleagues beautifully detail the many aspects of this macrophage immunometabolism.<span><sup>23</sup></span> They detail how amino acids such as arginine and methionine and their subsequent conversion within phagocytes impact continued uptake of additional corpses, macrophage responses, and in turn, disease processes. The authors also detail lactate regulation in macrophage responses, relevance to human disease such as atherosclerosis, and limitations to the current studies.</p><p>While phagocytes such as macrophages get a lot of attention as “professional phagocytes” capable of engulfing many corpses, there are also nonprofessional phagocytes. Although these phagocytes may do cell clearance with slower kinetics than macrophages, they play an important role in routine clearance of the many cells in the body. The retinal pigmented epithelial cells (RPE) of the retina provide a beautiful example, as they clear on a daily basis the “used” photoreceptors that are damaged from light during the day and they need to be removed to allow new photoreceptors to take their place.<span><sup>24, 25</sup></span> Another beautiful aspect of the RPE is that they are postmitotic, and we are born and die with the same number of RPE. This means that the RPE cells do the clearance throughout the lifetime, in addition to their many nurse cell functions for the photoreceptors to maintain a healthy retina. Silvia Finnemann and colleagues detail the background on clearance by RPE cells, the receptors, and mechanisms of RPE-mediated clearance, as well as diseases that arise when this clearance is disturbed and lead to retinal inflammation.<span><sup>26</sup></span></p><p>Just like we do not fully appreciate the importance of garbage workers until they go on strike, the importance of the “cellular clearance crew” has gotten much better appreciation in the past two decades when failures in clearance, or complexities associated with cell death and cell clearance contribute to inflammatory diseases or links to cancer.<span><sup>8</sup></span> This is detailed in four of the final chapters of this volume. First, Christopher Gregory details beautifully the complexity of cell death in the cancer context.<span><sup>27</sup></span> He details how apoptotic cells and their products (including extracellular vesicles and other factors released by the dying cells) regulate the tumor microenvironment; this includes how responses of the macrophages within solid tumors, either due to direct contact with the apoptotic cells or their released products, lead to reshaping the tumor microenvironment for tumor growth. This is followed by a detailed description by Wagoner, Michael Elliott, and colleagues on the antibody-mediated phagocytosis of tumor cells—which occurs when an antibody-bound tumor cell is recognized via Fc receptors, primarily by macrophages.<span><sup>28</sup></span> The authors also present challenges and modifications that occurs to the phagocytes as part of the FcR-mediated phagocytosis, and some approaches to overcome them.</p><p>It has become increasingly clear that many auto-inflammatory diseases such as atherosclerosis, arthritis, and certain forms of colitis have a component of defective or minimally the release of certain components from the late stage dying cells, that promote a pro-inflammatory milieu, and in turn, chronic inflammation.<span><sup>1</sup></span> Further, if some of the self-antigens are presented in this pro-inflammatory environment, this can evolve to autoimmunity. Schneider and Arandjelovic detail the inflammatory components of arthritis. Interestingly, some of the components of the engulfment machinery has additional roles, such as in neutrophil migration to the arthritic joints that in turn can also contribute to arthritis.<span><sup>29</sup></span> Lastly, Gabrielle Fredman and Sayeed Khan discuss the role of specialized pro-resolving mediators (SPMs) in clearance of dead cells.<span><sup>30</sup></span> They highlight the role of SPMs in facilitating clearance of not only apoptotic cells but also necroptotic cells, and further link these to non-resolving diseases such as atherosclerosis.</p><p>In sum, in the past couple of decades of investigations on how cells die, how they are removed, and the consequences of such regulated and efficient phagocytosis to homeostasis have exploded. This has led to a remarkable increase in knowledge on the molecules and mechanisms, and how defects in clearance contribute to disease states in specific tissue contexts. In this collection of reviews, the authors not only highlight contributions from their own laboratories, but they also put these discoveries in the larger context of what is known, the challenges, and how to go about addressing the next set of questions in the field. The research on cellular turnover, with a role in essentially every single tissue, is bound to continue, with modulating phagocytosis providing opportunities for treating multiple diseases.<span><sup>31</sup></span></p><p>The author declares no competing interests.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5000,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13285","citationCount":"0","resultStr":"{\"title\":\"Phagocytic clearance of dying cells and its implications\",\"authors\":\"Kodi S. Ravichandran\",\"doi\":\"10.1111/imr.13285\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>It is estimated that an average adult human turns over roughly 330 ± 20 billion cells every day as part of healthy living.<span><sup>1, 2</sup></span> This translates to 0.4% of our body mass. Such a large number for cell turnover then begs the question—what are these cells and why? The reasons for this are multi-factorial. First, there are cells in the body that have a finite life span, such as neutrophils (~1 day) and erythrocytes (~120 days), and there are also other cell types such as many hematopoietic cells that have a life span of a few days to few weeks; these need to be removed after their useful life span and replaced by new cells. Second, there are many aspects of development where we generate excess cells, of which only a few are deemed fit to progress to full maturation, and the rest undergo death and need to be removed; examples of this include development of T cells in the thymus, B cells in the bone marrow, and also adult neurogenesis in the brain.<span><sup>1</sup></span> Third, there are also “damaged” cells that emerge daily in the body, such as due to light/UV damage, for example skin and photoreceptors of the eye.<span><sup>3</sup></span> Thus, all these turnover events result in a large number of cells undergoing death essentially in all organs and tissues, albeit at different magnitude.<span><sup>2</sup></span> Although there are many different forms of death processes, the cells that are destined die via homeostatic turnover do so primarily via the process of caspase-dependent apoptosis.<span><sup>4</sup></span></p><p>What happens to these dying cells? Despite the billions of dying cells per day, when one looks at tissues, it is hard to recognize dying cells, even in those with high cellular turnover. This is because the recognition and clearance of dying cells is remarkably efficient.<span><sup>5, 6</sup></span> Just like there is a dedicated set of molecules and mechanisms to induce programmed cell death, we also possess a dedicated machinery to recognize and remove these dying cells.<span><sup>7</sup></span> Such clearance under homeostasis conditions occurs quickly, efficiently, and from an immunological perspective, quietly.<span><sup>8</sup></span> It is worth noting that just like the apoptotic cell death machinery, the clearance processes are also highly conserved evolutionarily, and studies from the nematode, flies, zebrafish, mice, and humans have established the conserved components of the clearance process.<span><sup>9, 10</sup></span> This volume of Immunological Reviews focuses on different aspects of the cell clearance process and its implications to homeostasis and disease.</p><p>While there are different forms of phagocytosis, the recognition and clearance of apoptotic cells by phagocytes has been termed “efferocytosis,” a term originally coined by Dr. Peter Henson. (where “effero” means “carry to the grave”).<span><sup>11</sup></span> This should be distinguished from Fc receptor mediated phagocytosis or complement receptor-mediated phagocytosis, which involves opsonization of target cells by specific ligands and uptake via the respective receptors. A key distinction from the other forms of phagocytosis is that the apoptotic cell clearance does not induce an immune response; further efferocytosis is also actively anti-inflammatory.<span><sup>8</sup></span> This makes sense when one considers the fact that if we were to induce an inflammatory response to billions of cells that we clear every day, we may all end up as walking bags of inflammation. However, the failure to clear the apoptotic cells promptly can induce secondary necrosis that can lead to inflammatory sequelae, as detailed by some of the chapters in this volume.</p><p>Works from a number of laboratories have now established that there are different steps to recognition and removal of dying cells.<span><sup>1, 12</sup></span> The first step is the recognition of the dying cells. When phagocytes such as macrophages, dendritic cells, or healthy neighbors are in close proximity to the dying cell, specific molecules on the apoptotic cells are recognized by specific receptors on the engulfing cell leading to subsequent intracellular signaling, cytoskeletal reorganization, and corpse internalization.<span><sup>13</sup></span> While there are many ligands exposed on cells undergoing apoptosis, the best detailed is the exposure of the phospholipid phosphatidylserine (PtdSer).<span><sup>14, 15</sup></span> PtdSer is normally kept via an active and energy dependent process on the inner leaflet but gets exposed on the outer leaflet as part of the apoptotic process.<span><sup>15, 16</sup></span> This PtdSer in turn, gets recognized by multiple PtdSer recognition receptors—either directly, or indirectly, via intermediary bridging molecules.<span><sup>16, 17</sup></span> As part of the first chapter, Dr. Tal Brustyn-Cohen details one of the best described receptor families linked to clearance of apoptotic cells, namely the TAM receptors.<span><sup>18</sup></span> These TAM receptors recognize PtdSer indirectly via Gas6 or Protein S that bind PtdSer, and this chapter details the role of TAM receptors in different contexts and highlights their role in other physiology.</p><p>One of the challenges in studying cell clearance in the mammals is that multiple homologues for engulfment receptors and signaling molecules, and the complexities that arise when individual knockouts do not often have a clear phenotype. Thus, defining the function of individual molecules, as well as visualizing cell death and clearance in vivo have been a challenge for the past couple of decades. Will Wood, Andrew Davidson, and colleagues detail the beautiful model systems for cell death and efferocytosis in the fruit fly Drosophila that have provided many new insights.<span><sup>19</sup></span> They also detail new approaches that have been developed to visualize apoptosis and efferocytosis in vivo, plus the different molecular mechanisms of clearance employed by Drosophila macrophages to clear dying cells.</p><p>After a phagocyte engulfs an apoptotic cell, a second challenge ensues—that is, digesting the corpse. This is no small feat, as this involves digesting another cell that is often nearly the same size as the phagocyte itself. Further, many phagocytes engulf multiple apoptotic cells.<span><sup>20</sup></span> Mylvaganam and Freeman take a comprehensive approach to how a phagocyte resolves a phagolysosome as well as aspects of the membrane traffic, and the role of solute carriers in managing some of the contents of the corpse. They also put this in disease contexts with lysosomal storage disorders.<span><sup>21</sup></span></p><p>Another inherent challenge that the phagocyte faces is how to handle all the excess biomass. To put it another way, when a phagocyte engulfs an apoptotic cell, it basically doubles its lipids, carbohydrates, and proteins, to name a few of the corpse contents. Further, phagocytes such as macrophages ingest multiple corpses in succession, leading to even greater challenge of dealing with all this excess metabolic overload.<span><sup>20, 22</sup></span> Shilperoort, Tabas, and colleagues beautifully detail the many aspects of this macrophage immunometabolism.<span><sup>23</sup></span> They detail how amino acids such as arginine and methionine and their subsequent conversion within phagocytes impact continued uptake of additional corpses, macrophage responses, and in turn, disease processes. The authors also detail lactate regulation in macrophage responses, relevance to human disease such as atherosclerosis, and limitations to the current studies.</p><p>While phagocytes such as macrophages get a lot of attention as “professional phagocytes” capable of engulfing many corpses, there are also nonprofessional phagocytes. Although these phagocytes may do cell clearance with slower kinetics than macrophages, they play an important role in routine clearance of the many cells in the body. The retinal pigmented epithelial cells (RPE) of the retina provide a beautiful example, as they clear on a daily basis the “used” photoreceptors that are damaged from light during the day and they need to be removed to allow new photoreceptors to take their place.<span><sup>24, 25</sup></span> Another beautiful aspect of the RPE is that they are postmitotic, and we are born and die with the same number of RPE. This means that the RPE cells do the clearance throughout the lifetime, in addition to their many nurse cell functions for the photoreceptors to maintain a healthy retina. Silvia Finnemann and colleagues detail the background on clearance by RPE cells, the receptors, and mechanisms of RPE-mediated clearance, as well as diseases that arise when this clearance is disturbed and lead to retinal inflammation.<span><sup>26</sup></span></p><p>Just like we do not fully appreciate the importance of garbage workers until they go on strike, the importance of the “cellular clearance crew” has gotten much better appreciation in the past two decades when failures in clearance, or complexities associated with cell death and cell clearance contribute to inflammatory diseases or links to cancer.<span><sup>8</sup></span> This is detailed in four of the final chapters of this volume. First, Christopher Gregory details beautifully the complexity of cell death in the cancer context.<span><sup>27</sup></span> He details how apoptotic cells and their products (including extracellular vesicles and other factors released by the dying cells) regulate the tumor microenvironment; this includes how responses of the macrophages within solid tumors, either due to direct contact with the apoptotic cells or their released products, lead to reshaping the tumor microenvironment for tumor growth. This is followed by a detailed description by Wagoner, Michael Elliott, and colleagues on the antibody-mediated phagocytosis of tumor cells—which occurs when an antibody-bound tumor cell is recognized via Fc receptors, primarily by macrophages.<span><sup>28</sup></span> The authors also present challenges and modifications that occurs to the phagocytes as part of the FcR-mediated phagocytosis, and some approaches to overcome them.</p><p>It has become increasingly clear that many auto-inflammatory diseases such as atherosclerosis, arthritis, and certain forms of colitis have a component of defective or minimally the release of certain components from the late stage dying cells, that promote a pro-inflammatory milieu, and in turn, chronic inflammation.<span><sup>1</sup></span> Further, if some of the self-antigens are presented in this pro-inflammatory environment, this can evolve to autoimmunity. Schneider and Arandjelovic detail the inflammatory components of arthritis. Interestingly, some of the components of the engulfment machinery has additional roles, such as in neutrophil migration to the arthritic joints that in turn can also contribute to arthritis.<span><sup>29</sup></span> Lastly, Gabrielle Fredman and Sayeed Khan discuss the role of specialized pro-resolving mediators (SPMs) in clearance of dead cells.<span><sup>30</sup></span> They highlight the role of SPMs in facilitating clearance of not only apoptotic cells but also necroptotic cells, and further link these to non-resolving diseases such as atherosclerosis.</p><p>In sum, in the past couple of decades of investigations on how cells die, how they are removed, and the consequences of such regulated and efficient phagocytosis to homeostasis have exploded. This has led to a remarkable increase in knowledge on the molecules and mechanisms, and how defects in clearance contribute to disease states in specific tissue contexts. In this collection of reviews, the authors not only highlight contributions from their own laboratories, but they also put these discoveries in the larger context of what is known, the challenges, and how to go about addressing the next set of questions in the field. The research on cellular turnover, with a role in essentially every single tissue, is bound to continue, with modulating phagocytosis providing opportunities for treating multiple diseases.<span><sup>31</sup></span></p><p>The author declares no competing interests.</p>\",\"PeriodicalId\":178,\"journal\":{\"name\":\"Immunological Reviews\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.5000,\"publicationDate\":\"2023-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13285\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunological Reviews\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/imr.13285\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunological Reviews","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/imr.13285","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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摘要

研究哺乳动物细胞清除率的挑战之一是吞噬受体和信号分子的多种同源物,以及当单个敲除时出现的复杂性,通常没有明确的表型。因此,在过去的几十年里,定义单个分子的功能,以及可视化体内细胞死亡和清除一直是一个挑战。Will Wood、Andrew Davidson及其同事详细介绍了果蝇细胞死亡和传出细胞增多的美丽模型系统,这些系统提供了许多新的见解。19他们还详细介绍了已开发的在体内观察细胞凋亡和传出细胞增生的新方法,以及果蝇巨噬细胞清除垂死细胞的不同分子机制。吞噬细胞吞噬凋亡细胞后,第二个挑战随之而来,即消化尸体。这不是一个小壮举,因为这涉及到消化另一个通常与吞噬细胞大小几乎相同的细胞。此外,许多吞噬细胞吞噬多个凋亡细胞。20 Mylvaganam和Freeman对吞噬细胞如何分解吞噬多胞体、膜交通的各个方面以及溶质载体在管理尸体某些内容物中的作用采取了全面的方法。他们还将此应用于溶酶体储存紊乱的疾病环境。21吞噬细胞面临的另一个固有挑战是如何处理所有多余的生物量。换句话说,当吞噬细胞吞噬凋亡细胞时,其脂质、碳水化合物和蛋白质基本上会翻倍,仅举一些尸体内容物的例子。此外,巨噬细胞等吞噬细胞连续吞噬多具尸体,这给处理所有这些过度代谢过载带来了更大的挑战。20,22 Shilperoort,Tabas,23他们详细介绍了精氨酸和甲硫氨酸等氨基酸及其随后在吞噬细胞内的转化如何影响额外尸体的持续摄取、巨噬细胞反应,进而影响疾病过程。作者还详细介绍了巨噬细胞反应中的乳酸调节,与动脉粥样硬化等人类疾病的相关性,以及当前研究的局限性。虽然巨噬细胞等吞噬细胞作为能够吞噬许多尸体的“专业吞噬细胞”受到了很多关注,但也有非专业吞噬细胞。尽管这些吞噬细胞可能以比巨噬细胞慢的动力学进行细胞清除,但它们在体内许多细胞的常规清除中发挥着重要作用。视网膜的视网膜色素上皮细胞(RPE)提供了一个很好的例子,因为它们每天都会清除白天因光照而受损的“已用”感光细胞,需要将其移除,以让新的感光细胞取而代之。24,25 RPE的另一个美丽方面是它们是有丝分裂后的,我们生下来和死下来都有相同数量的RPE。这意味着RPE细胞在一生中都会进行清除,除了它们对感光细胞的许多护理细胞功能外,还能维持健康的视网膜。Silvia Finnemann及其同事详细介绍了RPE细胞清除的背景、受体、RPE介导的清除机制,以及当这种清除受到干扰并导致视网膜炎症时出现的疾病。26就像我们在垃圾工人罢工之前没有充分认识到他们的重要性一样,在过去的二十年里,当清除失败或与细胞死亡和细胞清除相关的复杂性导致炎症性疾病或与癌症的联系时,“细胞清除小组”的重要性得到了更好的认识。首先,Christopher Gregory详细描述了癌症背景下细胞死亡的复杂性。27他详细描述了凋亡细胞及其产物(包括细胞外小泡和死亡细胞释放的其他因子)如何调节肿瘤微环境;这包括实体瘤内巨噬细胞的反应,无论是由于与凋亡细胞的直接接触还是其释放的产物,如何导致肿瘤微环境的重塑以促进肿瘤生长。Wagoner、Michael Elliott及其同事对抗体介导的肿瘤细胞吞噬作用进行了详细描述,当抗体结合的肿瘤细胞通过Fc受体(主要是巨噬细胞)被识别时,就会发生这种吞噬作用,以及克服这些问题的一些方法。 越来越清楚的是,许多自身炎症性疾病,如动脉粥样硬化、关节炎和某些形式的结肠炎,都有一种成分,即某些成分从晚期死亡细胞中有缺陷或最低限度地释放,从而促进促炎环境,进而引发慢性炎症。1此外,如果一些自身抗原在这种促炎环境中出现,这可能会演变为自身免疫。Schneider和Arandjelovic详细介绍了关节炎的炎症成分。有趣的是,吞噬机制的一些组成部分具有额外的作用,例如中性粒细胞迁移到关节炎关节,这反过来也会导致关节炎。29最后,加布里埃尔Fredman和Sayed Khan讨论了专门的促分解介质(SPM)在清除死细胞中的作用。30他们强调了SPM在促进细胞凋亡和坏死细胞清除方面的作用,并进一步将其与动脉粥样硬化等非分解疾病联系起来。总之,在过去的几十年里,对细胞如何死亡、如何去除以及这种调节和有效的吞噬作用对体内平衡的影响的研究已经爆炸式增长。这导致了对分子和机制的了解显著增加,以及清除缺陷如何在特定组织环境中导致疾病状态。在这组综述中,作者不仅强调了他们自己实验室的贡献,而且还将这些发现放在已知的、挑战以及如何解决该领域的下一组问题的更大背景下。对细胞更新的研究,基本上在每一个组织中都有作用,势必会继续下去,调节吞噬作用为治疗多种疾病提供了机会。31作者声明没有相互竞争的兴趣。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Phagocytic clearance of dying cells and its implications

It is estimated that an average adult human turns over roughly 330 ± 20 billion cells every day as part of healthy living.1, 2 This translates to 0.4% of our body mass. Such a large number for cell turnover then begs the question—what are these cells and why? The reasons for this are multi-factorial. First, there are cells in the body that have a finite life span, such as neutrophils (~1 day) and erythrocytes (~120 days), and there are also other cell types such as many hematopoietic cells that have a life span of a few days to few weeks; these need to be removed after their useful life span and replaced by new cells. Second, there are many aspects of development where we generate excess cells, of which only a few are deemed fit to progress to full maturation, and the rest undergo death and need to be removed; examples of this include development of T cells in the thymus, B cells in the bone marrow, and also adult neurogenesis in the brain.1 Third, there are also “damaged” cells that emerge daily in the body, such as due to light/UV damage, for example skin and photoreceptors of the eye.3 Thus, all these turnover events result in a large number of cells undergoing death essentially in all organs and tissues, albeit at different magnitude.2 Although there are many different forms of death processes, the cells that are destined die via homeostatic turnover do so primarily via the process of caspase-dependent apoptosis.4

What happens to these dying cells? Despite the billions of dying cells per day, when one looks at tissues, it is hard to recognize dying cells, even in those with high cellular turnover. This is because the recognition and clearance of dying cells is remarkably efficient.5, 6 Just like there is a dedicated set of molecules and mechanisms to induce programmed cell death, we also possess a dedicated machinery to recognize and remove these dying cells.7 Such clearance under homeostasis conditions occurs quickly, efficiently, and from an immunological perspective, quietly.8 It is worth noting that just like the apoptotic cell death machinery, the clearance processes are also highly conserved evolutionarily, and studies from the nematode, flies, zebrafish, mice, and humans have established the conserved components of the clearance process.9, 10 This volume of Immunological Reviews focuses on different aspects of the cell clearance process and its implications to homeostasis and disease.

While there are different forms of phagocytosis, the recognition and clearance of apoptotic cells by phagocytes has been termed “efferocytosis,” a term originally coined by Dr. Peter Henson. (where “effero” means “carry to the grave”).11 This should be distinguished from Fc receptor mediated phagocytosis or complement receptor-mediated phagocytosis, which involves opsonization of target cells by specific ligands and uptake via the respective receptors. A key distinction from the other forms of phagocytosis is that the apoptotic cell clearance does not induce an immune response; further efferocytosis is also actively anti-inflammatory.8 This makes sense when one considers the fact that if we were to induce an inflammatory response to billions of cells that we clear every day, we may all end up as walking bags of inflammation. However, the failure to clear the apoptotic cells promptly can induce secondary necrosis that can lead to inflammatory sequelae, as detailed by some of the chapters in this volume.

Works from a number of laboratories have now established that there are different steps to recognition and removal of dying cells.1, 12 The first step is the recognition of the dying cells. When phagocytes such as macrophages, dendritic cells, or healthy neighbors are in close proximity to the dying cell, specific molecules on the apoptotic cells are recognized by specific receptors on the engulfing cell leading to subsequent intracellular signaling, cytoskeletal reorganization, and corpse internalization.13 While there are many ligands exposed on cells undergoing apoptosis, the best detailed is the exposure of the phospholipid phosphatidylserine (PtdSer).14, 15 PtdSer is normally kept via an active and energy dependent process on the inner leaflet but gets exposed on the outer leaflet as part of the apoptotic process.15, 16 This PtdSer in turn, gets recognized by multiple PtdSer recognition receptors—either directly, or indirectly, via intermediary bridging molecules.16, 17 As part of the first chapter, Dr. Tal Brustyn-Cohen details one of the best described receptor families linked to clearance of apoptotic cells, namely the TAM receptors.18 These TAM receptors recognize PtdSer indirectly via Gas6 or Protein S that bind PtdSer, and this chapter details the role of TAM receptors in different contexts and highlights their role in other physiology.

One of the challenges in studying cell clearance in the mammals is that multiple homologues for engulfment receptors and signaling molecules, and the complexities that arise when individual knockouts do not often have a clear phenotype. Thus, defining the function of individual molecules, as well as visualizing cell death and clearance in vivo have been a challenge for the past couple of decades. Will Wood, Andrew Davidson, and colleagues detail the beautiful model systems for cell death and efferocytosis in the fruit fly Drosophila that have provided many new insights.19 They also detail new approaches that have been developed to visualize apoptosis and efferocytosis in vivo, plus the different molecular mechanisms of clearance employed by Drosophila macrophages to clear dying cells.

After a phagocyte engulfs an apoptotic cell, a second challenge ensues—that is, digesting the corpse. This is no small feat, as this involves digesting another cell that is often nearly the same size as the phagocyte itself. Further, many phagocytes engulf multiple apoptotic cells.20 Mylvaganam and Freeman take a comprehensive approach to how a phagocyte resolves a phagolysosome as well as aspects of the membrane traffic, and the role of solute carriers in managing some of the contents of the corpse. They also put this in disease contexts with lysosomal storage disorders.21

Another inherent challenge that the phagocyte faces is how to handle all the excess biomass. To put it another way, when a phagocyte engulfs an apoptotic cell, it basically doubles its lipids, carbohydrates, and proteins, to name a few of the corpse contents. Further, phagocytes such as macrophages ingest multiple corpses in succession, leading to even greater challenge of dealing with all this excess metabolic overload.20, 22 Shilperoort, Tabas, and colleagues beautifully detail the many aspects of this macrophage immunometabolism.23 They detail how amino acids such as arginine and methionine and their subsequent conversion within phagocytes impact continued uptake of additional corpses, macrophage responses, and in turn, disease processes. The authors also detail lactate regulation in macrophage responses, relevance to human disease such as atherosclerosis, and limitations to the current studies.

While phagocytes such as macrophages get a lot of attention as “professional phagocytes” capable of engulfing many corpses, there are also nonprofessional phagocytes. Although these phagocytes may do cell clearance with slower kinetics than macrophages, they play an important role in routine clearance of the many cells in the body. The retinal pigmented epithelial cells (RPE) of the retina provide a beautiful example, as they clear on a daily basis the “used” photoreceptors that are damaged from light during the day and they need to be removed to allow new photoreceptors to take their place.24, 25 Another beautiful aspect of the RPE is that they are postmitotic, and we are born and die with the same number of RPE. This means that the RPE cells do the clearance throughout the lifetime, in addition to their many nurse cell functions for the photoreceptors to maintain a healthy retina. Silvia Finnemann and colleagues detail the background on clearance by RPE cells, the receptors, and mechanisms of RPE-mediated clearance, as well as diseases that arise when this clearance is disturbed and lead to retinal inflammation.26

Just like we do not fully appreciate the importance of garbage workers until they go on strike, the importance of the “cellular clearance crew” has gotten much better appreciation in the past two decades when failures in clearance, or complexities associated with cell death and cell clearance contribute to inflammatory diseases or links to cancer.8 This is detailed in four of the final chapters of this volume. First, Christopher Gregory details beautifully the complexity of cell death in the cancer context.27 He details how apoptotic cells and their products (including extracellular vesicles and other factors released by the dying cells) regulate the tumor microenvironment; this includes how responses of the macrophages within solid tumors, either due to direct contact with the apoptotic cells or their released products, lead to reshaping the tumor microenvironment for tumor growth. This is followed by a detailed description by Wagoner, Michael Elliott, and colleagues on the antibody-mediated phagocytosis of tumor cells—which occurs when an antibody-bound tumor cell is recognized via Fc receptors, primarily by macrophages.28 The authors also present challenges and modifications that occurs to the phagocytes as part of the FcR-mediated phagocytosis, and some approaches to overcome them.

It has become increasingly clear that many auto-inflammatory diseases such as atherosclerosis, arthritis, and certain forms of colitis have a component of defective or minimally the release of certain components from the late stage dying cells, that promote a pro-inflammatory milieu, and in turn, chronic inflammation.1 Further, if some of the self-antigens are presented in this pro-inflammatory environment, this can evolve to autoimmunity. Schneider and Arandjelovic detail the inflammatory components of arthritis. Interestingly, some of the components of the engulfment machinery has additional roles, such as in neutrophil migration to the arthritic joints that in turn can also contribute to arthritis.29 Lastly, Gabrielle Fredman and Sayeed Khan discuss the role of specialized pro-resolving mediators (SPMs) in clearance of dead cells.30 They highlight the role of SPMs in facilitating clearance of not only apoptotic cells but also necroptotic cells, and further link these to non-resolving diseases such as atherosclerosis.

In sum, in the past couple of decades of investigations on how cells die, how they are removed, and the consequences of such regulated and efficient phagocytosis to homeostasis have exploded. This has led to a remarkable increase in knowledge on the molecules and mechanisms, and how defects in clearance contribute to disease states in specific tissue contexts. In this collection of reviews, the authors not only highlight contributions from their own laboratories, but they also put these discoveries in the larger context of what is known, the challenges, and how to go about addressing the next set of questions in the field. The research on cellular turnover, with a role in essentially every single tissue, is bound to continue, with modulating phagocytosis providing opportunities for treating multiple diseases.31

The author declares no competing interests.

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来源期刊
Immunological Reviews
Immunological Reviews 医学-免疫学
CiteScore
16.20
自引率
1.10%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Immunological Reviews is a specialized journal that focuses on various aspects of immunological research. It encompasses a wide range of topics, such as clinical immunology, experimental immunology, and investigations related to allergy and the immune system. The journal follows a unique approach where each volume is dedicated solely to a specific area of immunological research. However, collectively, these volumes aim to offer an extensive and up-to-date overview of the latest advancements in basic immunology and their practical implications in clinical settings.
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