The COVID-19 pandemic caused by the SARS-CoV-2 virus was arguably one of the worst public health disasters of the last 100 years. As many infectious disease experts were focused on influenza, MERS, ZIKA, or Ebola as potential pandemic-causing agents, SARS-CoV-2 appeared to come from nowhere and spread rapidly. As with any zoonotic agent, the initial pathogen was able to transmit to a new host (humans), but it was poorly adapted to the immune environment of the new host and resulted in a maladapted immune response. As the host-pathogen interaction evolved, subsequent variants of SARS-CoV-2 became less pathogenic and acquired immunity in the host provided protection, at least partial protection, to new variants. As the host-pathogen interaction has changed since the beginning of the pandemic, it is possible the clinical results discussed here may not be applicable today as they were at the start of the pandemic. With this caveat in mind, we present an overview of the immune response of severe COVID-19 from a clinical research perspective and examine clinical trials utilizing immunomodulating agents to further elucidate the importance of hyperinflammation as a factor contributing to severe COVID-19 disease.
{"title":"Lessons Learned From Clinical Trials of Immunotherapeutics for COVID-19.","authors":"Inyeong Lee, Christopher R Lupfer","doi":"10.1111/imr.13422","DOIUrl":"https://doi.org/10.1111/imr.13422","url":null,"abstract":"<p><p>The COVID-19 pandemic caused by the SARS-CoV-2 virus was arguably one of the worst public health disasters of the last 100 years. As many infectious disease experts were focused on influenza, MERS, ZIKA, or Ebola as potential pandemic-causing agents, SARS-CoV-2 appeared to come from nowhere and spread rapidly. As with any zoonotic agent, the initial pathogen was able to transmit to a new host (humans), but it was poorly adapted to the immune environment of the new host and resulted in a maladapted immune response. As the host-pathogen interaction evolved, subsequent variants of SARS-CoV-2 became less pathogenic and acquired immunity in the host provided protection, at least partial protection, to new variants. As the host-pathogen interaction has changed since the beginning of the pandemic, it is possible the clinical results discussed here may not be applicable today as they were at the start of the pandemic. With this caveat in mind, we present an overview of the immune response of severe COVID-19 from a clinical research perspective and examine clinical trials utilizing immunomodulating agents to further elucidate the importance of hyperinflammation as a factor contributing to severe COVID-19 disease.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reactive oxygen species (ROS) production and inflammasome activation are the key components of the innate immune response to microbial infection and sterile insults. ROS are at the intersection of inflammation and immunity during cancer development. Balanced regulation of ROS production and inflammasome activation serves as the central hub of innate immunity, determining whether a cell will survive or undergo cell death. However, the mechanisms underlying this balanced regulation remain unclear. Mitochondria and NADPH oxidases are the two major sources of ROS production. Recently, NCF4, a component of the NADPH oxidase complex that primarily contributes to ROS generation in phagocytes, was reported to balance ROS production and inflammasome activation in macrophages. The phosphorylation and puncta distribution of NCF4 shifts from the membrane-bound NADPH complex to the perinuclear region, promoting ASC speck formation and inflammasome activation, which triggers downstream IL-18-IFN-γ signaling to prevent the progression of colorectal cancer (CRC). Here, we review ROS signaling and inflammasome activation studies in colitis-associated CRC and propose that NCF4 acts as a ROS sensor that balances ROS production and inflammasome activation. In addition, NCF4 is a susceptibility gene for Crohn's disease (CD) and CRC. We discuss the evidence demonstrating NCF4's crucial role in facilitating cell-cell contact between immune cells and intestinal cells, and mediating the paracrine effects of inflammatory cytokines and ROS. This coordination of the signaling network helps create a robust immune microenvironment that effectively prevents epithelial cell mutagenesis and tumorigenesis during the early stage of colitis-associated CRC.
{"title":"Balanced regulation of ROS production and inflammasome activation in preventing early development of colorectal cancer.","authors":"Longjun Li, Tao Xu, Xiaopeng Qi","doi":"10.1111/imr.13417","DOIUrl":"https://doi.org/10.1111/imr.13417","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) production and inflammasome activation are the key components of the innate immune response to microbial infection and sterile insults. ROS are at the intersection of inflammation and immunity during cancer development. Balanced regulation of ROS production and inflammasome activation serves as the central hub of innate immunity, determining whether a cell will survive or undergo cell death. However, the mechanisms underlying this balanced regulation remain unclear. Mitochondria and NADPH oxidases are the two major sources of ROS production. Recently, NCF4, a component of the NADPH oxidase complex that primarily contributes to ROS generation in phagocytes, was reported to balance ROS production and inflammasome activation in macrophages. The phosphorylation and puncta distribution of NCF4 shifts from the membrane-bound NADPH complex to the perinuclear region, promoting ASC speck formation and inflammasome activation, which triggers downstream IL-18-IFN-γ signaling to prevent the progression of colorectal cancer (CRC). Here, we review ROS signaling and inflammasome activation studies in colitis-associated CRC and propose that NCF4 acts as a ROS sensor that balances ROS production and inflammasome activation. In addition, NCF4 is a susceptibility gene for Crohn's disease (CD) and CRC. We discuss the evidence demonstrating NCF4's crucial role in facilitating cell-cell contact between immune cells and intestinal cells, and mediating the paracrine effects of inflammatory cytokines and ROS. This coordination of the signaling network helps create a robust immune microenvironment that effectively prevents epithelial cell mutagenesis and tumorigenesis during the early stage of colitis-associated CRC.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epilepsy is a brain disorder characterized by recurrent seizures, which are brief episodes of abnormal electrical activity in the brain and involuntary movement that can lead to physical injury and loss of consciousness. Seizures are canonically accompanied by increased inflammatory cytokine production that promotes neuroinflammation, brain pathology, and seizure propagation. Understanding the source of pro-inflammatory cytokines which promote seizure pathogenesis could be a gateway to precision epilepsy drug design. This review discusses the inflammasome in epilepsy including its role in seizure propagation and negative impacts on brain health. The inflammasome is a multiprotein complex that coordinates IL-1β and IL-18 production in response to tissue damage, cellular stress, and infection. Clinical evidence for inflammasome signaling in epileptogenesis is reviewed followed by a discussion of emerging strategies to modulate inflammasome activity in epilepsy.
{"title":"Role of inflammasomes and neuroinflammation in epilepsy.","authors":"Ava Hollis, John R Lukens","doi":"10.1111/imr.13421","DOIUrl":"https://doi.org/10.1111/imr.13421","url":null,"abstract":"<p><p>Epilepsy is a brain disorder characterized by recurrent seizures, which are brief episodes of abnormal electrical activity in the brain and involuntary movement that can lead to physical injury and loss of consciousness. Seizures are canonically accompanied by increased inflammatory cytokine production that promotes neuroinflammation, brain pathology, and seizure propagation. Understanding the source of pro-inflammatory cytokines which promote seizure pathogenesis could be a gateway to precision epilepsy drug design. This review discusses the inflammasome in epilepsy including its role in seizure propagation and negative impacts on brain health. The inflammasome is a multiprotein complex that coordinates IL-1β and IL-18 production in response to tissue damage, cellular stress, and infection. Clinical evidence for inflammasome signaling in epileptogenesis is reviewed followed by a discussion of emerging strategies to modulate inflammasome activity in epilepsy.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer arises from the growth and division of uncontrolled erroneous cells. Programmed cell death (PCD), or regulated cell death (RCD), includes natural processes that eliminate damaged or abnormal cells. Dysregulation of PCD is a hallmark of cancer, as cancer cells often evade cell death and continue to proliferate. Exosomes nanoscale extracellular vesicles secreted by different types of cells carrying a variety of molecules, including nucleic acids, proteins, and lipids, to have indispensable role in the communication between cells, and can influence various cellular processes, including PCD. Exosomes have been shown to modulate PCD in cancer cells by transferring pro- or antideath molecules to neighboring cells. Additionally, exosomes can facilitate the spread of PCD to surrounding cancer cells, making them promising in the treatment of various cancers. The exosomes' diagnostic potential in cancer is also an active area of research. Exosomes can be isolated from a wide range of bodily fluids and tissues, such as blood and urine, and can provide a noninvasive way to monitor cancer progression and treatment response. Furthermore, exosomes have also been employed as a delivery system for therapeutic agents. By engineering exosomes to carry drugs or other therapeutic molecules, they can be targeted specifically to cancer cells, reducing toxicity to healthy tissues. Here, we discussed exosomes in the diagnosis and prevention of cancers, tumor immunotherapy, and drug delivery, as well as in different types of PCD.
{"title":"The role of exosomes in cancer-related programmed cell death","authors":"Xin Li, Zuoqian Jing, Xuejie Li, Lei Liu, Xiang Xiao, Yifan Zhong, Zihan Ren","doi":"10.1111/imr.13286","DOIUrl":"10.1111/imr.13286","url":null,"abstract":"<div>\u0000 \u0000 <p>Cancer arises from the growth and division of uncontrolled erroneous cells. Programmed cell death (PCD), or regulated cell death (RCD), includes natural processes that eliminate damaged or abnormal cells. Dysregulation of PCD is a hallmark of cancer, as cancer cells often evade cell death and continue to proliferate. Exosomes nanoscale extracellular vesicles secreted by different types of cells carrying a variety of molecules, including nucleic acids, proteins, and lipids, to have indispensable role in the communication between cells, and can influence various cellular processes, including PCD. Exosomes have been shown to modulate PCD in cancer cells by transferring pro- or antideath molecules to neighboring cells. Additionally, exosomes can facilitate the spread of PCD to surrounding cancer cells, making them promising in the treatment of various cancers. The exosomes' diagnostic potential in cancer is also an active area of research. Exosomes can be isolated from a wide range of bodily fluids and tissues, such as blood and urine, and can provide a noninvasive way to monitor cancer progression and treatment response. Furthermore, exosomes have also been employed as a delivery system for therapeutic agents. By engineering exosomes to carry drugs or other therapeutic molecules, they can be targeted specifically to cancer cells, reducing toxicity to healthy tissues. Here, we discussed exosomes in the diagnosis and prevention of cancers, tumor immunotherapy, and drug delivery, as well as in different types of PCD.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"321 1","pages":"169-180"},"PeriodicalIF":8.7,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72207666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Raquel S. Laureano, Isaure Vanmeerbeek, Jenny Sprooten, Jannes Govaerts, Stefan Naulaerts, Abhishek D. Garg
The cellular stress and immunity cycle is a cornerstone of organismal homeostasis. Stress activates intracellular and intercellular communications within a tissue or organ to initiate adaptive responses aiming to resolve the origin of this stress. If such local measures are unable to ameliorate this stress, then intercellular communications expand toward immune activation with the aim of recruiting immune cells to effectively resolve the situation while executing tissue repair to ameliorate any damage and facilitate homeostasis. This cellular stress-immunity cycle is severely dysregulated in diseased contexts like cancer. On one hand, cancer cells dysregulate the normal cellular stress responses to reorient them toward upholding growth at all costs, even at the expense of organismal integrity and homeostasis. On the other hand, the tumors severely dysregulate or inhibit various components of organismal immunity, for example, by facilitating immunosuppressive tumor landscape, lowering antigenicity, and increasing T-cell dysfunction. In this review we aim to comprehensively discuss the basis behind tumoral dysregulation of cellular stress-immunity cycle. We also offer insights into current understanding of the regulators and deregulators of this cycle and how they can be targeted for conceptualizing successful cancer immunotherapy regimen.
{"title":"The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy","authors":"Raquel S. Laureano, Isaure Vanmeerbeek, Jenny Sprooten, Jannes Govaerts, Stefan Naulaerts, Abhishek D. Garg","doi":"10.1111/imr.13287","DOIUrl":"10.1111/imr.13287","url":null,"abstract":"<div>\u0000 \u0000 <p>The cellular stress and immunity cycle is a cornerstone of organismal homeostasis. Stress activates intracellular and intercellular communications within a tissue or organ to initiate adaptive responses aiming to resolve the origin of this stress. If such local measures are unable to ameliorate this stress, then intercellular communications expand toward immune activation with the aim of recruiting immune cells to effectively resolve the situation while executing tissue repair to ameliorate any damage and facilitate homeostasis. This cellular stress-immunity cycle is severely dysregulated in diseased contexts like cancer. On one hand, cancer cells dysregulate the normal cellular stress responses to reorient them toward upholding growth at all costs, even at the expense of organismal integrity and homeostasis. On the other hand, the tumors severely dysregulate or inhibit various components of organismal immunity, for example, by facilitating immunosuppressive tumor landscape, lowering antigenicity, and increasing T-cell dysfunction. In this review we aim to comprehensively discuss the basis behind tumoral dysregulation of cellular stress-immunity cycle. We also offer insights into current understanding of the regulators and deregulators of this cycle and how they can be targeted for conceptualizing successful cancer immunotherapy regimen.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"321 1","pages":"71-93"},"PeriodicalIF":8.7,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71475038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiahan Le, Guangzhao Pan, Che Zhang, Yitao Chen, Amit K. Tiwari, Jiang-Jiang Qin
Ferroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron-dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis. Although chemotherapy is commonly used to treat GC, drug resistance often leads to poor therapeutic outcomes. In the last several years, extensive research on ferroptosis has highlighted its significant potential in GC therapy, providing a promising strategy to address drug resistance associated with standard cancer therapies. In this review, we offer an extensive summary of the key regulatory factors related to the mechanisms underlying ferroptosis. Various inducers and inhibitors specifically targeting ferroptosis are uncovered. Additionally, we explore the prospective applications and outcomes of these agents in the field of GC therapy, emphasizing their capacity to improve the outcomes of this patient population.
{"title":"Targeting ferroptosis in gastric cancer: Strategies and opportunities","authors":"Jiahan Le, Guangzhao Pan, Che Zhang, Yitao Chen, Amit K. Tiwari, Jiang-Jiang Qin","doi":"10.1111/imr.13280","DOIUrl":"10.1111/imr.13280","url":null,"abstract":"<div>\u0000 \u0000 <p>Ferroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron-dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis. Although chemotherapy is commonly used to treat GC, drug resistance often leads to poor therapeutic outcomes. In the last several years, extensive research on ferroptosis has highlighted its significant potential in GC therapy, providing a promising strategy to address drug resistance associated with standard cancer therapies. In this review, we offer an extensive summary of the key regulatory factors related to the mechanisms underlying ferroptosis. Various inducers and inhibitors specifically targeting ferroptosis are uncovered. Additionally, we explore the prospective applications and outcomes of these agents in the field of GC therapy, emphasizing their capacity to improve the outcomes of this patient population.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"321 1","pages":"228-245"},"PeriodicalIF":8.7,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ying Guo, Jin Zhou, Yaqi Wang, Xueliang Wu, Yakui Mou, Xicheng Song
Necroptosis is generally considered as an inflammatory cell death form. The core regulators of necroptotic signaling are receptor-interacting serine–threonine protein kinases 1 (RIPK1) and RIPK3, and the executioner, mixed lineage kinase domain-like pseudokinase (MLKL). Evidence demonstrates that necroptosis contributes profoundly to inflammatory respiratory diseases that are common public health problem. Necroptosis occurs in nearly all pulmonary cell types in the settings of inflammatory respiratory diseases. The influence of necroptosis on cells varies depending upon the type of cells, tissues, organs, etc., which is an important factor to consider. Thus, in this review, we briefly summarize the current state of knowledge regarding the biology of necroptosis, and focus on the key molecular mechanisms that define the necroptosis status of specific cell types in inflammatory respiratory diseases. We also discuss the clinical potential of small molecular inhibitors of necroptosis in treating inflammatory respiratory diseases, and describe the pathological processes that engage cross talk between necroptosis and other cell death pathways in the context of respiratory inflammation. The rapid advancement of single-cell technologies will help understand the key mechanisms underlying cell type-specific necroptosis that are critical to effectively treat pathogenic lung infections and inflammatory respiratory diseases.
{"title":"Cell type-specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases","authors":"Ying Guo, Jin Zhou, Yaqi Wang, Xueliang Wu, Yakui Mou, Xicheng Song","doi":"10.1111/imr.13282","DOIUrl":"10.1111/imr.13282","url":null,"abstract":"<div>\u0000 \u0000 <p>Necroptosis is generally considered as an inflammatory cell death form. The core regulators of necroptotic signaling are receptor-interacting serine–threonine protein kinases 1 (RIPK1) and RIPK3, and the executioner, mixed lineage kinase domain-like pseudokinase (MLKL). Evidence demonstrates that necroptosis contributes profoundly to inflammatory respiratory diseases that are common public health problem. Necroptosis occurs in nearly all pulmonary cell types in the settings of inflammatory respiratory diseases. The influence of necroptosis on cells varies depending upon the type of cells, tissues, organs, etc., which is an important factor to consider. Thus, in this review, we briefly summarize the current state of knowledge regarding the biology of necroptosis, and focus on the key molecular mechanisms that define the necroptosis status of specific cell types in inflammatory respiratory diseases. We also discuss the clinical potential of small molecular inhibitors of necroptosis in treating inflammatory respiratory diseases, and describe the pathological processes that engage cross talk between necroptosis and other cell death pathways in the context of respiratory inflammation. The rapid advancement of single-cell technologies will help understand the key mechanisms underlying cell type-specific necroptosis that are critical to effectively treat pathogenic lung infections and inflammatory respiratory diseases.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"321 1","pages":"52-70"},"PeriodicalIF":8.7,"publicationDate":"2023-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61559582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Immunology has long been the source of many significant medical breakthroughs, from vaccines for infections to therapeutics for cancer, autoimmunity, and transplant rejection. Indeed, the only diseases we have successfully eradicated, for example, smallpox and polio, were achieved through our understanding of the immune system. Furthermore, the immune system often plays an unexpected role in the outcome of a treatment not designed to engage the immune system. For instance, many chemotherapy or radiation therapies were initially designed to target cancer cells directly. However, subsequent investigations have uncovered the critical role these therapies have in stimulating the immune system.</p><p>As our understanding of the immune system deepens, its involvement in homeostasis and surveillance in almost every human organ becomes more apparent. For instance, the bidirectional response between the immune and central nervous systems has now been recognized as a major determinant for some neurodegenerative (e.g., Parkinson's disease) and psychiatric disorders. Other major chronic diseases, such as heart disease and diabetes, are influenced by the immune system. As such, the study of disease mechanisms would be deemed incomplete without considering the dynamic interaction of the aliment with the immune system. This recognition poses a significant challenge in understanding diseases, especially in humans, because studying the organ of interest is no longer sufficient to get the whole picture.</p><p>Due to its importance, many therapeutics have been developed to modulate the immune response for various diseases. A balance between activation and suppression is critical to maintaining a healthy, functional immune system. For instance, uncontrolled and overactive immune responses can lead to autoimmunity and tissue damage. Yet a hyporesponsive immune system can render the patient vulnerable to infection and cancer development. Many current therapies have been designed to either enhance or restrain the immune system. However, systemic immune system modulation tends to generate severe side effects. Therefore, precise spatiotemporal control of the immune response has become a major focus for the next generation of immunotherapy.</p><p>In this issue, 13 reviews have been prepared by some of the most innovative research groups describing the development of tools and strategies to harness the immune system for therapeutic applications. This issue will not be a comprehensive overview of immunoengineering. Instead, it will focus on applying protein and genetic engineering to improve the safety, specificity, and efficacy of immunotherapies. Furthermore, the immune system's direct interaction with almost all organs provides an intriguing opportunity for innovative and precise medical intervention. The immune system, while highly complex, is also very accessible. One can collect and genetically modify primary human immune cells, essentially converting them into sma
{"title":"Golden age of immunoengineering","authors":"Wilson W. Wong, Wendell A. Lim","doi":"10.1111/imr.13283","DOIUrl":"10.1111/imr.13283","url":null,"abstract":"<p>Immunology has long been the source of many significant medical breakthroughs, from vaccines for infections to therapeutics for cancer, autoimmunity, and transplant rejection. Indeed, the only diseases we have successfully eradicated, for example, smallpox and polio, were achieved through our understanding of the immune system. Furthermore, the immune system often plays an unexpected role in the outcome of a treatment not designed to engage the immune system. For instance, many chemotherapy or radiation therapies were initially designed to target cancer cells directly. However, subsequent investigations have uncovered the critical role these therapies have in stimulating the immune system.</p><p>As our understanding of the immune system deepens, its involvement in homeostasis and surveillance in almost every human organ becomes more apparent. For instance, the bidirectional response between the immune and central nervous systems has now been recognized as a major determinant for some neurodegenerative (e.g., Parkinson's disease) and psychiatric disorders. Other major chronic diseases, such as heart disease and diabetes, are influenced by the immune system. As such, the study of disease mechanisms would be deemed incomplete without considering the dynamic interaction of the aliment with the immune system. This recognition poses a significant challenge in understanding diseases, especially in humans, because studying the organ of interest is no longer sufficient to get the whole picture.</p><p>Due to its importance, many therapeutics have been developed to modulate the immune response for various diseases. A balance between activation and suppression is critical to maintaining a healthy, functional immune system. For instance, uncontrolled and overactive immune responses can lead to autoimmunity and tissue damage. Yet a hyporesponsive immune system can render the patient vulnerable to infection and cancer development. Many current therapies have been designed to either enhance or restrain the immune system. However, systemic immune system modulation tends to generate severe side effects. Therefore, precise spatiotemporal control of the immune response has become a major focus for the next generation of immunotherapy.</p><p>In this issue, 13 reviews have been prepared by some of the most innovative research groups describing the development of tools and strategies to harness the immune system for therapeutic applications. This issue will not be a comprehensive overview of immunoengineering. Instead, it will focus on applying protein and genetic engineering to improve the safety, specificity, and efficacy of immunotherapies. Furthermore, the immune system's direct interaction with almost all organs provides an intriguing opportunity for innovative and precise medical intervention. The immune system, while highly complex, is also very accessible. One can collect and genetically modify primary human immune cells, essentially converting them into sma","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"320 1","pages":"4-9"},"PeriodicalIF":8.7,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49687911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<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
{"title":"Phagocytic clearance of dying cells and its implications","authors":"Kodi S. Ravichandran","doi":"10.1111/imr.13285","DOIUrl":"10.1111/imr.13285","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 ","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"319 1","pages":"4-6"},"PeriodicalIF":8.7,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13285","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49672076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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