Pub Date : 2024-10-11DOI: 10.1038/s41577-024-01101-w
Lucy Bird
Febrile temperatures disrupt metabolism and induce DNA damage disproportionately in T helper 1 cell subsets. Cells that survive apoptosis and adapt by increasing their mitochondrial mass and DNA damage responses gain enhanced effector functions.
发热会破坏新陈代谢，并在 T 辅助细胞 1 亚群中诱发不成比例的 DNA 损伤。凋亡后存活下来的细胞会通过增加线粒体质量和 DNA 损伤反应来适应环境，从而增强效应功能。
{"title":"Fever affects T cell fate","authors":"Lucy Bird","doi":"10.1038/s41577-024-01101-w","DOIUrl":"10.1038/s41577-024-01101-w","url":null,"abstract":"Febrile temperatures disrupt metabolism and induce DNA damage disproportionately in T helper 1 cell subsets. Cells that survive apoptosis and adapt by increasing their mitochondrial mass and DNA damage responses gain enhanced effector functions.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1038/s41577-024-01097-3
Robert Thimme, Antonio Bertoletti, Matteo Iannacone
CD8+ T cells are crucial in controlling infection with hepatitis B virus (HBV) but are functionally impaired during chronic HBV infection. Traditionally, these functional deficits have been associated with classical T cell exhaustion due to persistent antigenic stimulation. However, recent findings challenge this concept, emphasizing the multifactorial nature of T cell dysfunction in HBV infection. CD8+ T cells are functionally impaired during chronic HBV infection. Recent findings from preclinical models and studies of chronically infected humans have revealed surprising insights into the nature of the T cell dysfunction, which may open new avenues for therapeutic intervention.
CD8+ T 细胞是控制乙型肝炎病毒（HBV）感染的关键，但在慢性 HBV 感染期间会出现功能障碍。传统上，这些功能障碍与持续抗原刺激导致的典型 T 细胞衰竭有关。然而，最近的研究结果挑战了这一概念，强调了在 HBV 感染中 T 细胞功能障碍的多因素性质。CD8+ T 细胞在慢性 HBV 感染期间功能受损。临床前模型和慢性感染人类研究的最新发现揭示了 T 细胞功能障碍的本质，这可能为治疗干预开辟了新的途径。
{"title":"Beyond exhaustion: the unique characteristics of CD8+ T cell dysfunction in chronic HBV infection","authors":"Robert Thimme, Antonio Bertoletti, Matteo Iannacone","doi":"10.1038/s41577-024-01097-3","DOIUrl":"10.1038/s41577-024-01097-3","url":null,"abstract":"CD8+ T cells are crucial in controlling infection with hepatitis B virus (HBV) but are functionally impaired during chronic HBV infection. Traditionally, these functional deficits have been associated with classical T cell exhaustion due to persistent antigenic stimulation. However, recent findings challenge this concept, emphasizing the multifactorial nature of T cell dysfunction in HBV infection. CD8+ T cells are functionally impaired during chronic HBV infection. Recent findings from preclinical models and studies of chronically infected humans have revealed surprising insights into the nature of the T cell dysfunction, which may open new avenues for therapeutic intervention.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1038/s41577-024-01087-5
Ananda Shanti Mirchandani, Manuel Alejandro Sanchez-Garcia, Sarah Ruth Walmsley
Most eukaryotes require oxygen for their survival and, with increasing multicellular complexity, oxygen availability and delivery rates vary across the tissues of complex organisms. In humans, healthy tissues have markedly different oxygen gradients, ranging from the hypoxic environment of the bone marrow (where our haematopoietic stem cells reside) to the lungs and their alveoli, which are among the most oxygenated areas of the body. Immune cells are therefore required to adapt to varying oxygen availability as they move from the bone marrow to peripheral organs to mediate their effector functions. These changing oxygen gradients are exaggerated during inflammation, where oxygenation is often depleted owing to alterations in tissue perfusion and increased cellular activity. As such, it is important to consider the effects of oxygenation on shaping the immune response during tissue homeostasis and disease conditions. In this Review, we address the relevance of both physiological oxygenation (physioxia) and disease-associated hypoxia (where cellular oxygen demand outstrips supply) for immune cell functions, discussing the relevance of hypoxia for immune responses in the settings of tissue homeostasis, inflammation, infection, cancer and disease immunotherapy. Oxygen levels vary throughout the body and immune cells must adapt to these changes, both during homeostasis and in disease. Here, the authors discuss the impact of physiological subatmospheric oxygen levels (physioxia) as well as disease-related hypoxia on immune cell responses. They consider the therapeutic relevance of understanding how oxygenation affects immune responses in various diseases, including tuberculosis, COVID-19 and cancer.
{"title":"How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia","authors":"Ananda Shanti Mirchandani, Manuel Alejandro Sanchez-Garcia, Sarah Ruth Walmsley","doi":"10.1038/s41577-024-01087-5","DOIUrl":"10.1038/s41577-024-01087-5","url":null,"abstract":"Most eukaryotes require oxygen for their survival and, with increasing multicellular complexity, oxygen availability and delivery rates vary across the tissues of complex organisms. In humans, healthy tissues have markedly different oxygen gradients, ranging from the hypoxic environment of the bone marrow (where our haematopoietic stem cells reside) to the lungs and their alveoli, which are among the most oxygenated areas of the body. Immune cells are therefore required to adapt to varying oxygen availability as they move from the bone marrow to peripheral organs to mediate their effector functions. These changing oxygen gradients are exaggerated during inflammation, where oxygenation is often depleted owing to alterations in tissue perfusion and increased cellular activity. As such, it is important to consider the effects of oxygenation on shaping the immune response during tissue homeostasis and disease conditions. In this Review, we address the relevance of both physiological oxygenation (physioxia) and disease-associated hypoxia (where cellular oxygen demand outstrips supply) for immune cell functions, discussing the relevance of hypoxia for immune responses in the settings of tissue homeostasis, inflammation, infection, cancer and disease immunotherapy. Oxygen levels vary throughout the body and immune cells must adapt to these changes, both during homeostasis and in disease. Here, the authors discuss the impact of physiological subatmospheric oxygen levels (physioxia) as well as disease-related hypoxia on immune cell responses. They consider the therapeutic relevance of understanding how oxygenation affects immune responses in various diseases, including tuberculosis, COVID-19 and cancer.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1038/s41577-024-01081-x
Satish Kumar Tiwari, Wei Jie Wong, Marco Moreira, Claudia Pasqualini, Florent Ginhoux
Macrophages are innate immune cells that are present in essentially all tissues, where they have vital roles in tissue development, homeostasis and pathogenesis. The importance of macrophages in tissue function is reflected by their association with various human diseases, and studying macrophage functions in both homeostasis and pathological tissue settings is a promising avenue for new targeted therapies that will improve human health. The ability to generate macrophages from induced pluripotent stem (iPS) cells has revolutionized macrophage biology, with the generation of iPS cell-derived macrophages (iMacs) providing unlimited access to genotype-specific cells that can be used to model various human diseases involving macrophage dysregulation. Such disease modelling is achieved by generating iPS cells from patient-derived cells carrying disease-related mutations or by introducing mutations into iPS cells from healthy donors using CRISPR–Cas9 technology. These iMacs that carry disease-related mutations can be used to study the aetiology of the particular disease in vitro. To achieve more physiological relevance, iMacs can be co-cultured in 2D systems with iPS cell-derived cells or in 3D systems with iPS cell-derived organoids. Here, we discuss the studies that have attempted to model various human diseases using iMacs, highlighting how these have advanced our knowledge about the role of macrophages in health and disease. Macrophages are associated with many human diseases but are challenging to study in vivo. Here, Ginhoux and colleagues discuss how iMacs — macrophages generated from induced pluripotent stem (iPS) cells — can enable disease modelling, including through the use of patient-derived iPS cells and 3D organoid co-culture systems. Ultimately, these iMac-based approaches can improve our understanding of macrophage biology in both health and disease.
{"title":"Induced pluripotent stem cell-derived macrophages as a platform for modelling human disease","authors":"Satish Kumar Tiwari, Wei Jie Wong, Marco Moreira, Claudia Pasqualini, Florent Ginhoux","doi":"10.1038/s41577-024-01081-x","DOIUrl":"10.1038/s41577-024-01081-x","url":null,"abstract":"Macrophages are innate immune cells that are present in essentially all tissues, where they have vital roles in tissue development, homeostasis and pathogenesis. The importance of macrophages in tissue function is reflected by their association with various human diseases, and studying macrophage functions in both homeostasis and pathological tissue settings is a promising avenue for new targeted therapies that will improve human health. The ability to generate macrophages from induced pluripotent stem (iPS) cells has revolutionized macrophage biology, with the generation of iPS cell-derived macrophages (iMacs) providing unlimited access to genotype-specific cells that can be used to model various human diseases involving macrophage dysregulation. Such disease modelling is achieved by generating iPS cells from patient-derived cells carrying disease-related mutations or by introducing mutations into iPS cells from healthy donors using CRISPR–Cas9 technology. These iMacs that carry disease-related mutations can be used to study the aetiology of the particular disease in vitro. To achieve more physiological relevance, iMacs can be co-cultured in 2D systems with iPS cell-derived cells or in 3D systems with iPS cell-derived organoids. Here, we discuss the studies that have attempted to model various human diseases using iMacs, highlighting how these have advanced our knowledge about the role of macrophages in health and disease. Macrophages are associated with many human diseases but are challenging to study in vivo. Here, Ginhoux and colleagues discuss how iMacs — macrophages generated from induced pluripotent stem (iPS) cells — can enable disease modelling, including through the use of patient-derived iPS cells and 3D organoid co-culture systems. Ultimately, these iMac-based approaches can improve our understanding of macrophage biology in both health and disease.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1038/s41577-024-01096-4
Yvonne Bordon
MICL regulates neutrophil responses by serving as an inhibitory pattern-recognition receptor for NETs.
MICL 通过作为 NET 的抑制性模式识别受体来调节中性粒细胞的反应。
{"title":"An inhibitory PRR reels in the neutrophil response to NETs","authors":"Yvonne Bordon","doi":"10.1038/s41577-024-01096-4","DOIUrl":"10.1038/s41577-024-01096-4","url":null,"abstract":"MICL regulates neutrophil responses by serving as an inhibitory pattern-recognition receptor for NETs.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1038/s41577-024-01094-6
Risa Ebina-Shibuya, Warren J. Leonard
{"title":"Publisher Correction: Role of thymic stromal lymphopoietin in allergy and beyond","authors":"Risa Ebina-Shibuya, Warren J. Leonard","doi":"10.1038/s41577-024-01094-6","DOIUrl":"10.1038/s41577-024-01094-6","url":null,"abstract":"","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41577-024-01094-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142314067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1038/s41577-024-01083-9
Thomas Boehm
Evolutionary immunology has entered a new era. Classical studies, using just a handful of model animal species, combined with clinical observations, provided an outline of how innate and adaptive immunity work together to ensure tissue homeostasis and to coordinate the fight against infections. However, revolutionary advances in cellular and molecular biology, genomics and methods of genetic modification now offer unprecedented opportunities. They provide immunologists with the possibility to consider, at unprecedented scale, the impact of the astounding phenotypic diversity of vertebrates on immune system function. This Perspective is intended to highlight some of the many interesting, but largely unexplored, biological phenomena that are related to immune function among the roughly 60,000 existing vertebrate species. Importantly, hypotheses arising from such wide-ranging comparative studies can be tested in representative and genetically tractable species. The emerging general principles and the discovery of their evolutionarily selected variations may inspire the future development of novel therapeutic strategies for human immune disorders. Technological advances in cellular and molecular immunology are providing unprecedented new insights into evolutionary immunology. This Perspective highlights new insights into the immune systems of different vertebrate species and discusses emerging general principles of immune system function.
{"title":"Understanding vertebrate immunity through comparative immunology","authors":"Thomas Boehm","doi":"10.1038/s41577-024-01083-9","DOIUrl":"10.1038/s41577-024-01083-9","url":null,"abstract":"Evolutionary immunology has entered a new era. Classical studies, using just a handful of model animal species, combined with clinical observations, provided an outline of how innate and adaptive immunity work together to ensure tissue homeostasis and to coordinate the fight against infections. However, revolutionary advances in cellular and molecular biology, genomics and methods of genetic modification now offer unprecedented opportunities. They provide immunologists with the possibility to consider, at unprecedented scale, the impact of the astounding phenotypic diversity of vertebrates on immune system function. This Perspective is intended to highlight some of the many interesting, but largely unexplored, biological phenomena that are related to immune function among the roughly 60,000 existing vertebrate species. Importantly, hypotheses arising from such wide-ranging comparative studies can be tested in representative and genetically tractable species. The emerging general principles and the discovery of their evolutionarily selected variations may inspire the future development of novel therapeutic strategies for human immune disorders. Technological advances in cellular and molecular immunology are providing unprecedented new insights into evolutionary immunology. This Perspective highlights new insights into the immune systems of different vertebrate species and discusses emerging general principles of immune system function.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1038/s41577-024-01095-5
Kirsty Minton
A study in Cell describes a platform to supply exogenous mitochondria to CD8+ T cells via nanotubes, which boosts their antitumour efficacy.
细胞》（Cell）杂志上的一项研究介绍了一种通过纳米管向 CD8+ T 细胞提供外源线粒体的平台，这种平台可提高它们的抗肿瘤功效。
{"title":"Mitochondrial tonic for adoptive T cell therapies","authors":"Kirsty Minton","doi":"10.1038/s41577-024-01095-5","DOIUrl":"10.1038/s41577-024-01095-5","url":null,"abstract":"A study in Cell describes a platform to supply exogenous mitochondria to CD8+ T cells via nanotubes, which boosts their antitumour efficacy.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1038/s41577-024-01076-8
Ludger Klein, Elisabetta Petrozziello
The extent of central T cell tolerance is determined by the diversity of self-antigens that developing thymocytes ‘see’ on thymic antigen-presenting cells (APCs). Here, focusing on insights from the past decade, we review the functional adaptations of medullary thymic epithelial cells, thymic dendritic cells and thymic B cells for the purpose of tolerance induction. Their distinct cellular characteristics range from unconventional phenomena, such as promiscuous gene expression or mimicry of peripheral cell types, to strategic positioning in distinct microenvironments and divergent propensities to preferentially access endogenous or exogenous antigen pools. We also discuss how ‘tonic’ inflammatory signals in the thymic microenvironment may extend the intrathymically visible ‘self’ to include autoantigens that are otherwise associated with highly immunogenic peripheral environments. For effective central T cell tolerance, developing thymocytes must encounter a diverse range of self-antigens presented by various thymic cells. Here, the authors describe how medullary thymic epithelial cells, dendritic cells and B cells are uniquely adapted through promiscuous gene expression, strategic positioning and inflammatory signals, which shape the peptide–MHC ligandomes and extend self-antigen visibility in the thymic microenvironment.
{"title":"Antigen presentation for central tolerance induction","authors":"Ludger Klein, Elisabetta Petrozziello","doi":"10.1038/s41577-024-01076-8","DOIUrl":"10.1038/s41577-024-01076-8","url":null,"abstract":"The extent of central T cell tolerance is determined by the diversity of self-antigens that developing thymocytes ‘see’ on thymic antigen-presenting cells (APCs). Here, focusing on insights from the past decade, we review the functional adaptations of medullary thymic epithelial cells, thymic dendritic cells and thymic B cells for the purpose of tolerance induction. Their distinct cellular characteristics range from unconventional phenomena, such as promiscuous gene expression or mimicry of peripheral cell types, to strategic positioning in distinct microenvironments and divergent propensities to preferentially access endogenous or exogenous antigen pools. We also discuss how ‘tonic’ inflammatory signals in the thymic microenvironment may extend the intrathymically visible ‘self’ to include autoantigens that are otherwise associated with highly immunogenic peripheral environments. For effective central T cell tolerance, developing thymocytes must encounter a diverse range of self-antigens presented by various thymic cells. Here, the authors describe how medullary thymic epithelial cells, dendritic cells and B cells are uniquely adapted through promiscuous gene expression, strategic positioning and inflammatory signals, which shape the peptide–MHC ligandomes and extend self-antigen visibility in the thymic microenvironment.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1038/s41577-024-01080-y
Matthew J. Sweet, Divya Ramnath, Amit Singhal, Ronan Kapetanovic
Macrophages destroy bacteria and other microorganisms through phagocytosis-coupled antimicrobial responses, such as the generation of reactive oxygen species and the delivery of hydrolytic enzymes from lysosomes to the phagosome. However, many intracellular bacteria subvert these responses, escaping to other cellular compartments to survive and/or replicate. Such bacterial subversion strategies are countered by a range of additional direct antibacterial responses that are switched on by pattern-recognition receptors and/or host-derived cytokines and other factors, often through inducible gene expression and/or metabolic reprogramming. Our understanding of these inducible antibacterial defence strategies in macrophages is rapidly evolving. In this Review, we provide an overview of the broad repertoire of antibacterial responses that can be engaged in macrophages, including LC3-associated phagocytosis, metabolic reprogramming and antimicrobial metabolites, lipid droplets, guanylate-binding proteins, antimicrobial peptides, metal ion toxicity, nutrient depletion, autophagy and nitric oxide production. We also highlight key inducers, signalling pathways and transcription factors involved in driving these different antibacterial responses. Finally, we discuss how a detailed understanding of the molecular mechanisms of antibacterial responses in macrophages might be exploited for developing host-directed therapies to combat antibiotic-resistant bacterial infections. Macrophages are innate immune sentinels providing frontline defence against infection. This Review describes the inducible mechanisms used by macrophages to kill bacterial pathogens and/or inhibit their growth and outlines how this knowledge might be exploited in the design of host-directed therapies.
{"title":"Inducible antibacterial responses in macrophages","authors":"Matthew J. Sweet, Divya Ramnath, Amit Singhal, Ronan Kapetanovic","doi":"10.1038/s41577-024-01080-y","DOIUrl":"10.1038/s41577-024-01080-y","url":null,"abstract":"Macrophages destroy bacteria and other microorganisms through phagocytosis-coupled antimicrobial responses, such as the generation of reactive oxygen species and the delivery of hydrolytic enzymes from lysosomes to the phagosome. However, many intracellular bacteria subvert these responses, escaping to other cellular compartments to survive and/or replicate. Such bacterial subversion strategies are countered by a range of additional direct antibacterial responses that are switched on by pattern-recognition receptors and/or host-derived cytokines and other factors, often through inducible gene expression and/or metabolic reprogramming. Our understanding of these inducible antibacterial defence strategies in macrophages is rapidly evolving. In this Review, we provide an overview of the broad repertoire of antibacterial responses that can be engaged in macrophages, including LC3-associated phagocytosis, metabolic reprogramming and antimicrobial metabolites, lipid droplets, guanylate-binding proteins, antimicrobial peptides, metal ion toxicity, nutrient depletion, autophagy and nitric oxide production. We also highlight key inducers, signalling pathways and transcription factors involved in driving these different antibacterial responses. Finally, we discuss how a detailed understanding of the molecular mechanisms of antibacterial responses in macrophages might be exploited for developing host-directed therapies to combat antibiotic-resistant bacterial infections. Macrophages are innate immune sentinels providing frontline defence against infection. This Review describes the inducible mechanisms used by macrophages to kill bacterial pathogens and/or inhibit their growth and outlines how this knowledge might be exploited in the design of host-directed therapies.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":67.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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