Mast cells are infamous for mediating allergic and inflammatory diseases due to their capacity of rapidly releasing a wide range of inflammatory mediators stored in cytoplasmic granules. However, mast cells also have several important physiological roles that involve selective and agonist-specific release of these active mediators. While a filtering mechanism at the plasma membrane could regulate the selective release of some cargo, the plethora of stored cargo and the diversity of mast cell functions suggests the existence of granule subtypes with distinct trafficking pathways. The molecular mechanisms underlying differential trafficking and exocytosis of these granules are not known, neither is it clear how granule trafficking is coupled to the stimulus. In endothelial cells, a Rab GTPase, Rab46, responds to histamine but not thrombin signals, and this regulates the trafficking of a subpopulation of endothelial-specific granules. Here, we sought to explore, for the first time, if Rab46 plays a role in mast cell function. We demonstrate that Rab46 is highly expressed in human and murine mast cells, and Rab46 genetic deletion has an effect on mast cell degranulation that depends on both stimuli and mast cell subtype. This initial insight into the contribution of Rab46 to mast cell function and the understanding of the role of Rab46 in stimuli-dependent trafficking in other cell types necessitates further investigations of Rab46 in mast cell granular trafficking so that novel and specific therapeutic targets for treatment of the diverse pathologies mediated by mast cells can be developed.
{"title":"Rab46: a novel player in mast cell function.","authors":"Lucia Pedicini, Jessica Smith, Sinisa Savic, Lynn McKeown","doi":"10.1093/discim/kyad028","DOIUrl":"https://doi.org/10.1093/discim/kyad028","url":null,"abstract":"<p><p>Mast cells are infamous for mediating allergic and inflammatory diseases due to their capacity of rapidly releasing a wide range of inflammatory mediators stored in cytoplasmic granules. However, mast cells also have several important physiological roles that involve selective and agonist-specific release of these active mediators. While a filtering mechanism at the plasma membrane could regulate the selective release of some cargo, the plethora of stored cargo and the diversity of mast cell functions suggests the existence of granule subtypes with distinct trafficking pathways. The molecular mechanisms underlying differential trafficking and exocytosis of these granules are not known, neither is it clear how granule trafficking is coupled to the stimulus. In endothelial cells, a Rab GTPase, Rab46, responds to histamine but not thrombin signals, and this regulates the trafficking of a subpopulation of endothelial-specific granules. Here, we sought to explore, for the first time, if Rab46 plays a role in mast cell function. We demonstrate that Rab46 is highly expressed in human and murine mast cells, and Rab46 genetic deletion has an effect on mast cell degranulation that depends on both stimuli and mast cell subtype. This initial insight into the contribution of Rab46 to mast cell function and the understanding of the role of Rab46 in stimuli-dependent trafficking in other cell types necessitates further investigations of Rab46 in mast cell granular trafficking so that novel and specific therapeutic targets for treatment of the diverse pathologies mediated by mast cells can be developed.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"3 1","pages":"kyad028"},"PeriodicalIF":0.0,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140860771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-04eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad027
Sally A Clayton, Chloe Lockwood, John D O'Neil, Kalbinder K Daley, Sofia Hain, Dina Abdelmottaleb, Oliwia O Bolimowska, Daniel A Tennant, Andrew R Clark
Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization.
{"title":"The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.","authors":"Sally A Clayton, Chloe Lockwood, John D O'Neil, Kalbinder K Daley, Sofia Hain, Dina Abdelmottaleb, Oliwia O Bolimowska, Daniel A Tennant, Andrew R Clark","doi":"10.1093/discim/kyad027","DOIUrl":"10.1093/discim/kyad027","url":null,"abstract":"<p><p>Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"2 1","pages":"kyad027"},"PeriodicalIF":0.0,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Garrod-Ketchley, Laure Mourgue d'Algue, Katie Littlewood, Gillian Hood, Anne Worthington, Melanie Pattrick, Caroline Sutcliffe, Zoi Valla, Noorshad Joti, Udeshi Zalak, Amy Edwards, Sarah Finer, S. Henson
CD4+ T cells are essential for protection from viral pathogens, such as SARS-CoV-2. However, an increase in the dysfunction CD4+ EMRA subset is likely to hinder the immune response towards viruses. We show here that CD4+ EMRAs are increased with elevated blood glucose, such as people living with T2D, which alters mitochondrial function and causes the differentiation of CD4+ T cells, reducing the immune response to COVID-19 vaccination. CD4+ T cells were examined for senescence, their insulin dynamics, and mitochondrial function after in vitro culture of high and low glucose media, with or without rotenone or mitoQ. Serum samples were used to assess circulating inflammation and IgG antibodies to SARS-CoV-2. People living with T2D had increased expression of CD4+ EMRA T cells, the appearance of which correlated with increasing blood glucose values. The T2D cohort showed a reduced mitochondrial membrane potential and increased mtROS production. These results were mimicked using high glucose media which accelerated CD4+ T cell differentiation and reduced MMP. People living with T2D (non-hyperglycaemic and hyperglycaemic) had altered expression of inflammatory mediators. CD4+ EMRA cells did not respond to COVID-19 peptides, and people with T2D had a reduced T cell and antibody response to SARS-CoV-2 S1 spike protein. We have shown that senescent-like CD4+ EMRA influence the viral response in SARS-CoV-2 and that CD4+ EMRAs may arise from faulty mitochondrial dynamics due to increased environmental glucose. Further study is required to determine the direct link increased glucose has with CD4+ EMRA formation.
CD4+ T 细胞是抵御 SARS-CoV-2 等病毒病原体的关键。然而，功能障碍 CD4+ EMRA 亚群的增加可能会阻碍对病毒的免疫反应。我们在此表明，CD4+ EMRA 会随着血糖升高而增加，例如患有 T2D 的人，血糖升高会改变线粒体功能，导致 CD4+ T 细胞分化，从而降低对 COVID-19 疫苗接种的免疫反应。在使用或不使用鱼藤酮或 mitoQ 的情况下，CD4+ T 细胞经过高、低葡萄糖培养基的体外培养后，其衰老、胰岛素动态和线粒体功能得到了检测。血清样本用于评估循环炎症和 SARS-CoV-2 IgG 抗体。患有 T2D 的人的 CD4+ EMRA T 细胞表达增加，其出现与血糖值的增加有关。T2D人群的线粒体膜电位降低，mtROS生成增加。使用高糖培养基可模拟这些结果，因为高糖培养基可加速 CD4+ T 细胞分化并减少 MMP。T2D患者（非高血糖和高血糖）的炎症介质表达发生了改变。CD4+ EMRA细胞对COVID-19多肽没有反应，T2D患者的T细胞和抗体对SARS-CoV-2 S1尖峰蛋白的反应减弱。我们已经证明，衰老样 CD4+ EMRA 会影响 SARS-CoV-2 的病毒反应，而 CD4+ EMRA 可能是由于环境中葡萄糖增加导致线粒体动力学发生故障而产生的。要确定葡萄糖增加与 CD4+ EMRA 形成之间的直接联系，还需要进一步研究。
{"title":"The generation of senescent-like CD4+ EMRA T cells in T2D and their contribution to poor COVID-19 vaccine responses","authors":"C. Garrod-Ketchley, Laure Mourgue d'Algue, Katie Littlewood, Gillian Hood, Anne Worthington, Melanie Pattrick, Caroline Sutcliffe, Zoi Valla, Noorshad Joti, Udeshi Zalak, Amy Edwards, Sarah Finer, S. Henson","doi":"10.1093/discim/kyad026","DOIUrl":"https://doi.org/10.1093/discim/kyad026","url":null,"abstract":"CD4+ T cells are essential for protection from viral pathogens, such as SARS-CoV-2. However, an increase in the dysfunction CD4+ EMRA subset is likely to hinder the immune response towards viruses. We show here that CD4+ EMRAs are increased with elevated blood glucose, such as people living with T2D, which alters mitochondrial function and causes the differentiation of CD4+ T cells, reducing the immune response to COVID-19 vaccination. CD4+ T cells were examined for senescence, their insulin dynamics, and mitochondrial function after in vitro culture of high and low glucose media, with or without rotenone or mitoQ. Serum samples were used to assess circulating inflammation and IgG antibodies to SARS-CoV-2. People living with T2D had increased expression of CD4+ EMRA T cells, the appearance of which correlated with increasing blood glucose values. The T2D cohort showed a reduced mitochondrial membrane potential and increased mtROS production. These results were mimicked using high glucose media which accelerated CD4+ T cell differentiation and reduced MMP. People living with T2D (non-hyperglycaemic and hyperglycaemic) had altered expression of inflammatory mediators. CD4+ EMRA cells did not respond to COVID-19 peptides, and people with T2D had a reduced T cell and antibody response to SARS-CoV-2 S1 spike protein. We have shown that senescent-like CD4+ EMRA influence the viral response in SARS-CoV-2 and that CD4+ EMRAs may arise from faulty mitochondrial dynamics due to increased environmental glucose. Further study is required to determine the direct link increased glucose has with CD4+ EMRA formation.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139216519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"T cell and bacterial microbiota interaction at intestinal and skin epithelial interfaces","authors":"Damian Maseda, S. Manfredo-Vieira, Aimee S Payne","doi":"10.1093/discim/kyad024","DOIUrl":"https://doi.org/10.1093/discim/kyad024","url":null,"abstract":"also increased in mouse models","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"14 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139237760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The gut microbiome is an assemblage of microbes that have profound effects on their hosts. The composition of the microbiome is affected by bottom-up, among-taxa interactions and by top-down, host effects, which includes the host immune response. While the high-level composition of the microbiome is generally stable over time, component strains and genotypes will constantly be evolving, with both bottom-up and top-down effects acting as selection pressures, so driving microbial evolution. Secretory IgA is a major feature of the gut’s adaptive immune response, and a substantial proportion of gut bacteria are coated with IgA, though the effect of this on bacteria is unclear. Here we hypothesise that IgA binding to gut bacteria is a selection pressure that will drive the evolution of IgA-bound bacteria, so that they will have a different evolutionary trajectory than those bacteria not bound by IgA. We know very little about the microbiome of wild animals and even less about their gut immune responses, but it must be a priority to investigate this hypothesis to understand if and how host immune responses contribute to microbiome evolution.
肠道微生物组是对宿主产生深远影响的微生物集合体。微生物组的组成受到自下而上的微生物间相互作用和自上而下的宿主效应（包括宿主免疫反应）的影响。虽然微生物组的高层次组成随着时间的推移一般是稳定的，但其组成菌株和基因型会不断演变，自下而上和自上而下的影响都会成为选择压力，从而推动微生物的进化。分泌型 IgA 是肠道适应性免疫反应的一个主要特征，相当一部分肠道细菌被 IgA 包被，但这对细菌的影响尚不清楚。在这里，我们假设肠道细菌与 IgA 的结合是一种选择压力，它将推动与 IgA 结合的细菌的进化，因此它们的进化轨迹将与那些没有被 IgA 结合的细菌不同。我们对野生动物的微生物组知之甚少，对它们的肠道免疫反应更是一无所知，但我们必须优先研究这一假设，以了解宿主免疫反应是否以及如何促进微生物组的进化。
{"title":"Gut immune responses and evolution of the gut microbiome – a hypothesis","authors":"Marcus W. Viney, Louise Cheynel","doi":"10.1093/discim/kyad025","DOIUrl":"https://doi.org/10.1093/discim/kyad025","url":null,"abstract":"The gut microbiome is an assemblage of microbes that have profound effects on their hosts. The composition of the microbiome is affected by bottom-up, among-taxa interactions and by top-down, host effects, which includes the host immune response. While the high-level composition of the microbiome is generally stable over time, component strains and genotypes will constantly be evolving, with both bottom-up and top-down effects acting as selection pressures, so driving microbial evolution. Secretory IgA is a major feature of the gut’s adaptive immune response, and a substantial proportion of gut bacteria are coated with IgA, though the effect of this on bacteria is unclear. Here we hypothesise that IgA binding to gut bacteria is a selection pressure that will drive the evolution of IgA-bound bacteria, so that they will have a different evolutionary trajectory than those bacteria not bound by IgA. We know very little about the microbiome of wild animals and even less about their gut immune responses, but it must be a priority to investigate this hypothesis to understand if and how host immune responses contribute to microbiome evolution.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139245146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katarzyna Knop, C. Gómez-Moreira, Alison Galloway, Dimitrinka Ditsova, V. Cowling
On T cell activation, upregulation of gene expression produces the protein required for the differentiation and proliferation of effector cell populations. RAM, the co-factor of the RNA cap methyltransferase RNMT, is upregulated following activation. Formation of the RNA cap protects RNA during synthesis and guides RNA processing and translation. Using conditional gene deletion, we found that Ram expression stabilises RNMT protein in T cells and is required for its upregulation on activation. When the Ram gene is deleted in naïve T cells, there are major impacts on activation-induced RNA cap formation and gene expression. Activated T cell proliferation is dependent on increased ribosome production; in Ram knock-out T cells activation-induced expression of ribosomal protein genes and snoRNAs is most severely reduced. Consistent with these changes, Ram deletion resulted in reduced protein synthesis, and reduced growth and proliferation of CD4 T cells. Deletion of Ram results in a similar but milder phenotype to Rnmt deletion, supporting the role of RAM as a RNMT co-factor.
T 细胞激活后，基因表达上调，产生效应细胞群分化和增殖所需的蛋白质。RAM是RNA帽甲基转移酶RNMT的辅助因子，在激活后上调。RNA 帽的形成可在合成过程中保护 RNA，并引导 RNA 的加工和翻译。通过条件性基因缺失，我们发现Ram的表达能稳定T细胞中的RNMT蛋白，并且是其激活时上调所必需的。当删除幼稚T细胞中的Ram基因时，会对活化诱导的RNA帽形成和基因表达产生重大影响。活化 T 细胞的增殖依赖于核糖体产量的增加；在敲除 Ram 基因的 T 细胞中，活化诱导的核糖体蛋白基因和 snoRNA 的表达严重减少。与这些变化一致的是，Ram 基因缺失导致蛋白质合成减少，CD4 T 细胞的生长和增殖减少。Ram缺失导致的表型与Rnmt缺失类似，但较为温和，这支持了RAM作为RNMT辅助因子的作用。
{"title":"RAM is upregulated during T cell activation and is required for RNA cap formation and gene expression","authors":"Katarzyna Knop, C. Gómez-Moreira, Alison Galloway, Dimitrinka Ditsova, V. Cowling","doi":"10.1093/discim/kyad021","DOIUrl":"https://doi.org/10.1093/discim/kyad021","url":null,"abstract":"On T cell activation, upregulation of gene expression produces the protein required for the differentiation and proliferation of effector cell populations. RAM, the co-factor of the RNA cap methyltransferase RNMT, is upregulated following activation. Formation of the RNA cap protects RNA during synthesis and guides RNA processing and translation. Using conditional gene deletion, we found that Ram expression stabilises RNMT protein in T cells and is required for its upregulation on activation. When the Ram gene is deleted in naïve T cells, there are major impacts on activation-induced RNA cap formation and gene expression. Activated T cell proliferation is dependent on increased ribosome production; in Ram knock-out T cells activation-induced expression of ribosomal protein genes and snoRNAs is most severely reduced. Consistent with these changes, Ram deletion resulted in reduced protein synthesis, and reduced growth and proliferation of CD4 T cells. Deletion of Ram results in a similar but milder phenotype to Rnmt deletion, supporting the role of RAM as a RNMT co-factor.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"54 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139265082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain metastases (BrM) develop in 20 to 40% of patients with advanced cancer. They mainly originate from lung cancer, melanoma, breast cancer and renal cell carcinoma, and are associated with a poor prognosis. While patients with BrM traditionally lack effective treatment options, immunotherapy is increasingly gaining in importance in this group of patients, with clinical trials in the past decade demonstrating efficacy and safety of immune checkpoint blockade in BrM originating from specific tumor types, foremost melanoma. The brain is an immune-specialized environment with several unique molecular, cellular, and anatomical features that affect immune responses, including those against tumors. In this review we discuss the potential role that some of these unique characteristics may play in the efficacy of immunotherapy, mainly focusing on the lymphatic drainage in the brain and the role of systemic anti-tumor immunity that develops due to the presence of concurrent extracranial disease in addition to BrM.
{"title":"Immunotherapy in the context of immune-specialized environment of brain metastases","authors":"F. James, M. Lorger","doi":"10.1093/discim/kyad023","DOIUrl":"https://doi.org/10.1093/discim/kyad023","url":null,"abstract":"Brain metastases (BrM) develop in 20 to 40% of patients with advanced cancer. They mainly originate from lung cancer, melanoma, breast cancer and renal cell carcinoma, and are associated with a poor prognosis. While patients with BrM traditionally lack effective treatment options, immunotherapy is increasingly gaining in importance in this group of patients, with clinical trials in the past decade demonstrating efficacy and safety of immune checkpoint blockade in BrM originating from specific tumor types, foremost melanoma. The brain is an immune-specialized environment with several unique molecular, cellular, and anatomical features that affect immune responses, including those against tumors. In this review we discuss the potential role that some of these unique characteristics may play in the efficacy of immunotherapy, mainly focusing on the lymphatic drainage in the brain and the role of systemic anti-tumor immunity that develops due to the presence of concurrent extracranial disease in addition to BrM.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"8 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139268488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Despite the rising prevalence and costs for the society, obesity etiology and its precise cellular and molecular mechanisms are still insufficiently understood. The excessive accumulation of fat by adipocytes plays a key role in obesity progression and has many repercussions on total body physiology. In recent years the immune system as a gatekeeper of adipose tissue homeostasis has been evidenced and has become a focal point of research. Herein we focus on eosinophils, an important component of type 2 immunity, assuming fundamental, yet ill-defined, roles in the genesis and progression of obesity and related metabolic disorders. We summarise eosinophilopoiesis and eosinophils recruitment into adipose tissue and discuss how adipose tissue environment shape their function and vice versa. Finally, we also detail how obesity transforms the local eosinophil niche. Understanding eosinophil crosstalk with the diverse cell types within the adipose tissue environment will allow us to framework the therapeutic potential of eosinophils in obesity.
{"title":"Eosinophils in obesity and obesity-associated disorders","authors":"Yanan Hu, Svetoslav Chakarov","doi":"10.1093/discim/kyad022","DOIUrl":"https://doi.org/10.1093/discim/kyad022","url":null,"abstract":"Abstract Despite the rising prevalence and costs for the society, obesity etiology and its precise cellular and molecular mechanisms are still insufficiently understood. The excessive accumulation of fat by adipocytes plays a key role in obesity progression and has many repercussions on total body physiology. In recent years the immune system as a gatekeeper of adipose tissue homeostasis has been evidenced and has become a focal point of research. Herein we focus on eosinophils, an important component of type 2 immunity, assuming fundamental, yet ill-defined, roles in the genesis and progression of obesity and related metabolic disorders. We summarise eosinophilopoiesis and eosinophils recruitment into adipose tissue and discuss how adipose tissue environment shape their function and vice versa. Finally, we also detail how obesity transforms the local eosinophil niche. Understanding eosinophil crosstalk with the diverse cell types within the adipose tissue environment will allow us to framework the therapeutic potential of eosinophils in obesity.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"101 9","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134957614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Karolina Bentkowska, Alex Hardgrave, Nadia Iqbal, Laura Gresty, Bethany Marsden, Sheila Macharia, Lucy Jackson-Jones
Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease predominated by auto-antibodies that recognise cellular components. Pleural involvement is the most common SLE-related lung disease. Natural antibodies are rapidly secreted by innate-like B cells following perturbation of homeostasis and are important in the early stages of immune activation. The serous cavities are home to large numbers of innate-like B cells present both within serous fluid and resident within fat-associated lymphoid clusters (FALCs). FALCs are important hubs for B-cell activation and local antibody secretion within the body cavities. Patients with SLE can develop anti-phospholipid antibodies and in rare situations develop alveolar haemorrhage. Utilising delivery of the hydrocarbon oil pristane in C57BL/6 mice as a model of SLE we identify a rapid expansion of pleural cavity B cells as early as day 3 after intra-peritoneal pristane delivery. Following pristane delivery, pericardial B1 B cells are proliferative, express the plasma-cell surface marker CD138 and secrete both innate and class switched antibodies highlighting that this cavity niche may play an unrecognised role in the initiation of lupus pleuritis.
{"title":"Pericardial & Mediastinal Fat-Associated Lymphoid Clusters are rapidly activated in an alkane induced model of Systemic Lupus Erythematosus","authors":"Karolina Bentkowska, Alex Hardgrave, Nadia Iqbal, Laura Gresty, Bethany Marsden, Sheila Macharia, Lucy Jackson-Jones","doi":"10.1093/discim/kyad017","DOIUrl":"https://doi.org/10.1093/discim/kyad017","url":null,"abstract":"Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease predominated by auto-antibodies that recognise cellular components. Pleural involvement is the most common SLE-related lung disease. Natural antibodies are rapidly secreted by innate-like B cells following perturbation of homeostasis and are important in the early stages of immune activation. The serous cavities are home to large numbers of innate-like B cells present both within serous fluid and resident within fat-associated lymphoid clusters (FALCs). FALCs are important hubs for B-cell activation and local antibody secretion within the body cavities. Patients with SLE can develop anti-phospholipid antibodies and in rare situations develop alveolar haemorrhage. Utilising delivery of the hydrocarbon oil pristane in C57BL/6 mice as a model of SLE we identify a rapid expansion of pleural cavity B cells as early as day 3 after intra-peritoneal pristane delivery. Following pristane delivery, pericardial B1 B cells are proliferative, express the plasma-cell surface marker CD138 and secrete both innate and class switched antibodies highlighting that this cavity niche may play an unrecognised role in the initiation of lupus pleuritis.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135864884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chi-Ching Tung, Abhay P S Rathore, Ashley L St. John
Abstract Mast cells (MCs) are multifunctional immune cells that express a diverse repertoire of surface receptors and pre-stored bioactive mediators. They are traditionally recognized for their involvement in allergic and inflammatory responses, yet there is a growing body of literature highlighting their contributions to mounting adaptive immune responses. In particular, there is growing evidence that MCs can serve as antigen presenting cells (APCs), owing to their often close proximity to T cells in both lymphoid organs and peripheral tissues. Recent studies have provided compelling support for this concept, by demonstrating the presence of antigen processing and presentation machinery in MCs and their ability to engage in classical and non-classical pathways of antigen presentation. However, there remain discrepancies and unresolved questions regarding the extent of the MC’s capabilities with respect to antigen presentation. In this review, we discuss our current understanding of the antigen presentation by MCs and its influence on adaptive immunity.
{"title":"Conventional and non-conventional antigen presentation by mast cells","authors":"Chi-Ching Tung, Abhay P S Rathore, Ashley L St. John","doi":"10.1093/discim/kyad016","DOIUrl":"https://doi.org/10.1093/discim/kyad016","url":null,"abstract":"Abstract Mast cells (MCs) are multifunctional immune cells that express a diverse repertoire of surface receptors and pre-stored bioactive mediators. They are traditionally recognized for their involvement in allergic and inflammatory responses, yet there is a growing body of literature highlighting their contributions to mounting adaptive immune responses. In particular, there is growing evidence that MCs can serve as antigen presenting cells (APCs), owing to their often close proximity to T cells in both lymphoid organs and peripheral tissues. Recent studies have provided compelling support for this concept, by demonstrating the presence of antigen processing and presentation machinery in MCs and their ability to engage in classical and non-classical pathways of antigen presentation. However, there remain discrepancies and unresolved questions regarding the extent of the MC’s capabilities with respect to antigen presentation. In this review, we discuss our current understanding of the antigen presentation by MCs and its influence on adaptive immunity.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"12 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135061332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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