Pub Date : 2024-08-12DOI: 10.1038/s41423-024-01207-0
Lei Peng, Giacomo Sferruzza, Luojia Yang, Liqun Zhou, Sidi Chen
In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients. CAR-natural killer (CAR-NK) cell complements CAR-T cell therapy by offering several distinct advantages. CAR-NK cells do not require HLA compatibility and exhibit low safety concerns. Moreover, CAR-NK cells are conducive to “off-the-shelf” therapeutics, providing significant logistic advantages over CAR-T cells. Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies. However, their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration, as well as an immuno-suppressive tumor microenvironment. In this review, we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies, with a specific focus on the obstacles to their application in solid tumors. We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization. Finally, we explore future perspectives of these adoptive immunotherapies, highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.
{"title":"CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors","authors":"Lei Peng, Giacomo Sferruzza, Luojia Yang, Liqun Zhou, Sidi Chen","doi":"10.1038/s41423-024-01207-0","DOIUrl":"10.1038/s41423-024-01207-0","url":null,"abstract":"In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients. CAR-natural killer (CAR-NK) cell complements CAR-T cell therapy by offering several distinct advantages. CAR-NK cells do not require HLA compatibility and exhibit low safety concerns. Moreover, CAR-NK cells are conducive to “off-the-shelf” therapeutics, providing significant logistic advantages over CAR-T cells. Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies. However, their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration, as well as an immuno-suppressive tumor microenvironment. In this review, we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies, with a specific focus on the obstacles to their application in solid tumors. We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization. Finally, we explore future perspectives of these adoptive immunotherapies, highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 10","pages":"1089-1108"},"PeriodicalIF":21.8,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01207-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141930051","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 : 2024-08-12DOI: 10.1038/s41423-024-01206-1
Thomas J. C. Collins, Pooranee K. Morgan, Kevin Man, Graeme I. Lancaster, Andrew J. Murphy
The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.
{"title":"The influence of metabolic disorders on adaptive immunity","authors":"Thomas J. C. Collins, Pooranee K. Morgan, Kevin Man, Graeme I. Lancaster, Andrew J. Murphy","doi":"10.1038/s41423-024-01206-1","DOIUrl":"10.1038/s41423-024-01206-1","url":null,"abstract":"The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 10","pages":"1109-1119"},"PeriodicalIF":21.8,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141930049","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 : 2024-08-12DOI: 10.1038/s41423-024-01205-2
Hangyu Liu, Min Wu, Qiangqiang Wang, Liuchuang Gao, Han Jiang, Ketai Shi, Yawen Lin, Junyi Zhou, Ju Huang, Shen Qu, Yuwei Zhang, Fang Zheng, Yafei Huang, Junyan Han
Epithelial-derived cytokines, especially type 2 alarmins (TSLP, IL-25, and IL-33), have emerged as critical mediators of type 2 inflammation. IL-33 attracts more interest for its strong association with allergic asthma, especially in childhood asthma. However, the age-dependent role of IL-33 to the development of allergic asthma remains elusive. Here, using OVA-induced allergic asthma model in neonatal and adult mice, we report that IL-33 is the most important alarmin in neonatal lung both at steady state or inflammation. The deficiency of IL-33/ST2 abrogated the development of allergic asthma only in neonates, whereas in adults the effect was limited. Interestingly, the deficiency of IL-33/ST2 equally dampened the ILC2 responses in both neonatal and adult models. However, the effect of IL-33/ST2 deficiency on Th2 responses is age-dependent, which is only blocked in neonates. Furthermore, IL-33/ST2 signaling is dispensable for OVA sensitization. Following OVA challenge in adults, the deficiency of IL-33/ST2 results in compensational more TSLP, which in turn recruits and activates lung DCs and boosts Th2 responses. The enriched γδ T17 cells in IL-33/ST2 deficient neonatal lung suppress the expression of type 2 alarmins, CCL20 and GM-CSF via IL-17A, thus might confer the inhibition of allergic asthma. Finally, on the basis of IL-33 deficiency, the additive protective effects of TSLP blocking is much more pronounced than IL-25 blocking in adults. Our studies demonstrate that the role of IL-33 for ILC2 and Th2 responses varies among ages in OVA models and indicate that the factor of age should be considered for intervention of asthma.
{"title":"IL-33 released during challenge phase regulates allergic asthma in an age-dependent way","authors":"Hangyu Liu, Min Wu, Qiangqiang Wang, Liuchuang Gao, Han Jiang, Ketai Shi, Yawen Lin, Junyi Zhou, Ju Huang, Shen Qu, Yuwei Zhang, Fang Zheng, Yafei Huang, Junyan Han","doi":"10.1038/s41423-024-01205-2","DOIUrl":"https://doi.org/10.1038/s41423-024-01205-2","url":null,"abstract":"<p>Epithelial-derived cytokines, especially type 2 alarmins (TSLP, IL-25, and IL-33), have emerged as critical mediators of type 2 inflammation. IL-33 attracts more interest for its strong association with allergic asthma, especially in childhood asthma. However, the age-dependent role of IL-33 to the development of allergic asthma remains elusive. Here, using OVA-induced allergic asthma model in neonatal and adult mice, we report that IL-33 is the most important alarmin in neonatal lung both at steady state or inflammation. The deficiency of IL-33/ST2 abrogated the development of allergic asthma only in neonates, whereas in adults the effect was limited. Interestingly, the deficiency of IL-33/ST2 equally dampened the ILC2 responses in both neonatal and adult models. However, the effect of IL-33/ST2 deficiency on Th2 responses is age-dependent, which is only blocked in neonates. Furthermore, IL-33/ST2 signaling is dispensable for OVA sensitization. Following OVA challenge in adults, the deficiency of IL-33/ST2 results in compensational more TSLP, which in turn recruits and activates lung DCs and boosts Th2 responses. The enriched γδ T17 cells in IL-33/ST2 deficient neonatal lung suppress the expression of type 2 alarmins, CCL20 and GM-CSF via IL-17A, thus might confer the inhibition of allergic asthma. Finally, on the basis of IL-33 deficiency, the additive protective effects of TSLP blocking is much more pronounced than IL-25 blocking in adults. Our studies demonstrate that the role of IL-33 for ILC2 and Th2 responses varies among ages in OVA models and indicate that the factor of age should be considered for intervention of asthma.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"46 1","pages":""},"PeriodicalIF":24.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141930050","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 : 2024-08-12DOI: 10.1038/s41423-024-01186-2
Andrea Mihalić, Jelena Železnjak, Berislav Lisnić, Stipan Jonjić, Vanda Juranić Lisnić, Ilija Brizić
Cytomegalovirus (CMV), a representative member of the Betaherpesvirinae subfamily of herpesviruses, is common in the human population, but immunocompetent individuals are generally asymptomatic when infected with this virus. However, in immunocompromised individuals and immunologically immature fetuses and newborns, CMV can cause a wide range of often long-lasting morbidities and even death. CMV is not only widespread throughout the population but it is also widespread in its hosts, infecting and establishing latency in nearly all tissues and organs. Thus, understanding the pathogenesis of and immune responses to this virus is a prerequisite for developing effective prevention and treatment strategies. Multiple arms of the immune system are engaged to contain the infection, and general concepts of immune control of CMV are now reasonably well understood. Nonetheless, in recent years, tissue-specific immune responses have emerged as an essential factor for resolving CMV infection. As tissues differ in biology and function, so do immune responses to CMV and pathological processes during infection. This review discusses state-of-the-art knowledge of the immune response to CMV infection in tissues, with particular emphasis on several well-studied and most commonly affected organs.
{"title":"Immune surveillance of cytomegalovirus in tissues","authors":"Andrea Mihalić, Jelena Železnjak, Berislav Lisnić, Stipan Jonjić, Vanda Juranić Lisnić, Ilija Brizić","doi":"10.1038/s41423-024-01186-2","DOIUrl":"10.1038/s41423-024-01186-2","url":null,"abstract":"Cytomegalovirus (CMV), a representative member of the Betaherpesvirinae subfamily of herpesviruses, is common in the human population, but immunocompetent individuals are generally asymptomatic when infected with this virus. However, in immunocompromised individuals and immunologically immature fetuses and newborns, CMV can cause a wide range of often long-lasting morbidities and even death. CMV is not only widespread throughout the population but it is also widespread in its hosts, infecting and establishing latency in nearly all tissues and organs. Thus, understanding the pathogenesis of and immune responses to this virus is a prerequisite for developing effective prevention and treatment strategies. Multiple arms of the immune system are engaged to contain the infection, and general concepts of immune control of CMV are now reasonably well understood. Nonetheless, in recent years, tissue-specific immune responses have emerged as an essential factor for resolving CMV infection. As tissues differ in biology and function, so do immune responses to CMV and pathological processes during infection. This review discusses state-of-the-art knowledge of the immune response to CMV infection in tissues, with particular emphasis on several well-studied and most commonly affected organs.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 9","pages":"959-981"},"PeriodicalIF":21.8,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01186-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141949447","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 : 2024-08-06DOI: 10.1038/s41423-024-01192-4
Felix M. Wensveen, Marko Šestan, Bojan Polić
Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.
{"title":"The immunology of sickness metabolism","authors":"Felix M. Wensveen, Marko Šestan, Bojan Polić","doi":"10.1038/s41423-024-01192-4","DOIUrl":"10.1038/s41423-024-01192-4","url":null,"abstract":"Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 9","pages":"1051-1065"},"PeriodicalIF":21.8,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01192-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896937","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 : 2024-07-29DOI: 10.1038/s41423-024-01201-6
Peng Zhang, Qianjin Lu
{"title":"Author Correction: Genetic and epigenetic influences on the loss of tolerance in autoimmunity","authors":"Peng Zhang, Qianjin Lu","doi":"10.1038/s41423-024-01201-6","DOIUrl":"10.1038/s41423-024-01201-6","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 9","pages":"1082-1082"},"PeriodicalIF":21.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01201-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792080","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}
Brain tumors such as glioblastomas are resistant to immune checkpoint blockade therapy, largely due to limited T cell infiltration in the tumors. Here, we show that mice bearing intracranial tumors exhibit systemic immunosuppression and T cell sequestration in bone marrow, leading to reduced T cell infiltration in brain tumors. Elevated plasma corticosterone drives the T cell sequestration via glucocorticoid receptors in tumor-bearing mice. Immunosuppression mediated by glucocorticoid-induced T cell dynamics and the subsequent tumor growth promotion can be abrogated by adrenalectomy, the administration of glucocorticoid activation inhibitors or glucocorticoid receptor antagonists, and in mice with T cell-specific deletion of glucocorticoid receptor. CCR8 expression in T cells is increased in tumor-bearing mice in a glucocorticoid receptor-dependent manner. Additionally, chemokines CCL1 and CCL8, the ligands for CCR8, are highly expressed in bone marrow immune cells in tumor-bearing mice to recruit T cells. These findings suggested that brain tumor-induced glucocorticoid surge and CCR8 upregulation in T cells lead to T cell sequestration in bone marrow, impairing the anti-tumor immune response. Targeting the glucocorticoid receptor-CCR8 axis may offer a promising immunotherapeutic approach for the treatment of intracranial tumors.
胶质母细胞瘤等脑肿瘤对免疫检查点阻断疗法具有抗药性，这主要是由于肿瘤中的 T 细胞浸润有限。在这里，我们发现颅内肿瘤小鼠表现出全身免疫抑制和骨髓中的T细胞封存，导致脑肿瘤中的T细胞浸润减少。血浆中皮质酮的升高通过糖皮质激素受体驱动肿瘤小鼠的T细胞封存。肾上腺切除术、糖皮质激素活化抑制剂或糖皮质激素受体拮抗剂以及T细胞特异性糖皮质激素受体缺失的小鼠均可减轻糖皮质激素诱导的T细胞动力学介导的免疫抑制以及随后的肿瘤生长促进作用。肿瘤小鼠 T 细胞中 CCR8 的表达以糖皮质激素受体依赖的方式增加。此外，CCR8 的配体趋化因子 CCL1 和 CCL8 在肿瘤小鼠骨髓免疫细胞中高表达，以招募 T 细胞。这些研究结果表明，脑肿瘤诱导的糖皮质激素激增和T细胞中CCR8的上调会导致T细胞在骨髓中固着，从而损害抗肿瘤免疫反应。以糖皮质激素受体-CCR8轴为靶点可能为治疗颅内肿瘤提供一种前景广阔的免疫治疗方法。
{"title":"Targeting the glucocorticoid receptor-CCR8 axis mediated bone marrow T cell sequestration enhances infiltration of anti-tumor T cells in intracranial cancers","authors":"Jia Zhang, Yuzhu Shi, Xiaotong Xue, Wenqing Bu, Yanan Li, Tingting Yang, Lijuan Cao, Jiankai Fang, Peishan Li, Yongjing Chen, Zhen Li, Changshun Shao, Yufang Shi","doi":"10.1038/s41423-024-01202-5","DOIUrl":"10.1038/s41423-024-01202-5","url":null,"abstract":"Brain tumors such as glioblastomas are resistant to immune checkpoint blockade therapy, largely due to limited T cell infiltration in the tumors. Here, we show that mice bearing intracranial tumors exhibit systemic immunosuppression and T cell sequestration in bone marrow, leading to reduced T cell infiltration in brain tumors. Elevated plasma corticosterone drives the T cell sequestration via glucocorticoid receptors in tumor-bearing mice. Immunosuppression mediated by glucocorticoid-induced T cell dynamics and the subsequent tumor growth promotion can be abrogated by adrenalectomy, the administration of glucocorticoid activation inhibitors or glucocorticoid receptor antagonists, and in mice with T cell-specific deletion of glucocorticoid receptor. CCR8 expression in T cells is increased in tumor-bearing mice in a glucocorticoid receptor-dependent manner. Additionally, chemokines CCL1 and CCL8, the ligands for CCR8, are highly expressed in bone marrow immune cells in tumor-bearing mice to recruit T cells. These findings suggested that brain tumor-induced glucocorticoid surge and CCR8 upregulation in T cells lead to T cell sequestration in bone marrow, impairing the anti-tumor immune response. Targeting the glucocorticoid receptor-CCR8 axis may offer a promising immunotherapeutic approach for the treatment of intracranial tumors.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 10","pages":"1145-1157"},"PeriodicalIF":21.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751217","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}
Sterile neuroinflammation is a major driver of multiple neurological diseases. Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies, but the mechanism is poorly understood. Here, we showed that lysophosphatidylserine (LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation. Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS. Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling. In vivo, reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke. Thus, our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation, and suggest it as a potential therapeutic target for demyelination-associated diseases.
{"title":"GPR34 senses demyelination to promote neuroinflammation and pathologies","authors":"Bolong Lin, Yubo Zhou, Zonghui Huang, Ming Ma, Minghui Qi, Zhongjun Jiang, Guoyang Li, Yueli Xu, Jiaxian Yan, Di Wang, Xiaqiong Wang, Wei Jiang, Rongbin Zhou","doi":"10.1038/s41423-024-01204-3","DOIUrl":"10.1038/s41423-024-01204-3","url":null,"abstract":"Sterile neuroinflammation is a major driver of multiple neurological diseases. Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies, but the mechanism is poorly understood. Here, we showed that lysophosphatidylserine (LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation. Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS. Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling. In vivo, reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke. Thus, our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation, and suggest it as a potential therapeutic target for demyelination-associated diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 10","pages":"1131-1144"},"PeriodicalIF":21.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726972","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 : 2024-07-12DOI: 10.1038/s41423-024-01181-7
Andreas Pavlou, Felix Mulenge, Olivia Luise Gern, Lena Mareike Busker, Elisabeth Greimel, Inken Waltl, Ulrich Kalinke
Many newly emerging and re-emerging viruses have neuroinvasive potential, underscoring viral encephalitis as a global research priority. Upon entry of the virus into the CNS, severe neurological life-threatening conditions may manifest that are associated with high morbidity and mortality. The currently available therapeutic arsenal against viral encephalitis is rather limited, emphasizing the need to better understand the conditions of local antiviral immunity within the infected CNS. In this review, we discuss new insights into the pathophysiology of viral encephalitis, with a focus on myeloid cells and CD8+ T cells, which critically contribute to protection against viral CNS infection. By illuminating the prerequisites of myeloid and T cell activation, discussing new discoveries regarding their transcriptional signatures, and dissecting the mechanisms of their recruitment to sites of viral replication within the CNS, we aim to further delineate the complexity of antiviral responses within the infected CNS. Moreover, we summarize the current knowledge in the field of virus infection and neurodegeneration and discuss the potential links of some neurotropic viruses with certain pathological hallmarks observed in neurodegeneration.
许多新出现和再次出现的病毒都有可能侵入神经系统，因此病毒性脑炎成为全球研究的重点。病毒进入中枢神经系统后，可能会出现严重的神经系统症状，危及生命，发病率和死亡率都很高。目前针对病毒性脑炎的治疗手段非常有限，因此需要更好地了解受感染的中枢神经系统内局部抗病毒免疫的条件。在这篇综述中，我们讨论了对病毒性脑炎病理生理学的新认识，重点是骨髓细胞和 CD8+ T 细胞，它们对保护中枢神经系统免受病毒感染起着至关重要的作用。通过阐明髓系细胞和 T 细胞活化的先决条件、讨论有关其转录特征的新发现以及剖析它们被招募到中枢神经系统内病毒复制位点的机制，我们旨在进一步阐明受感染的中枢神经系统内抗病毒反应的复杂性。此外，我们还总结了病毒感染和神经变性领域的现有知识，并讨论了一些神经滋养病毒与神经变性中观察到的某些病理特征之间的潜在联系。
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