Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.
{"title":"Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS","authors":"Changchang Xu, Lin Zhang, Shaoyu Xu, Zichen Wang, Qi Han, Ying Lv, Xingfang Wang, Xiangxin Zhang, Qingju Zhang, Ying Zhang, Simeng He, Qiuhuan Yuan, Yuan Bian, Chuanbao Li, Jiali Wang, Feng Xu, Yihai Cao, Jiaojiao Pang, Yuguo Chen","doi":"10.1038/s41423-024-01146-w","DOIUrl":"10.1038/s41423-024-01146-w","url":null,"abstract":"Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 5","pages":"510-526"},"PeriodicalIF":24.1,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109527","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 : 2024-03-08DOI: 10.1038/s41423-024-01147-9
Zvi G. Fridlender, Zvi Granot
{"title":"Neutrophils in the tumor microenvironment – when a company becomes a crowd","authors":"Zvi G. Fridlender, Zvi Granot","doi":"10.1038/s41423-024-01147-9","DOIUrl":"10.1038/s41423-024-01147-9","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 4","pages":"313-314"},"PeriodicalIF":24.1,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01147-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140064998","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 : 2024-03-08DOI: 10.1038/s41423-024-01140-2
Mohammed Al-Talib, Sandra Dimonte, Ian R. Humphreys
Mucosal surfaces that line the respiratory, gastrointestinal and genitourinary tracts are the major interfaces between the immune system and the environment. Their unique immunological landscape is characterized by the necessity of balancing tolerance to commensal microorganisms and other innocuous exposures against protection from pathogenic threats such as viruses. Numerous pathogenic viruses, including herpesviruses and retroviruses, exploit this environment to establish chronic infection. Effector and regulatory T-cell populations, including effector and resident memory T cells, play instrumental roles in mediating the transition from acute to chronic infection, where a degree of viral replication is tolerated to minimize immunopathology. Persistent antigen exposure during chronic viral infection leads to the evolution and divergence of these responses. In this review, we discuss advances in the understanding of mucosal T-cell immunity during chronic viral infections and how features of T-cell responses develop in different chronic viral infections of the mucosa. We consider how insights into T-cell immunity at mucosal surfaces could inform vaccine strategies: not only to protect hosts from chronic viral infections but also to exploit viruses that can persist within mucosal surfaces as vaccine vectors.
呼吸道、胃肠道和泌尿生殖道的粘膜表面是免疫系统与环境之间的主要界面。其独特的免疫学特征是，必须在对共生微生物和其他无害接触的耐受性与对病毒等致病威胁的保护之间取得平衡。包括疱疹病毒和逆转录病毒在内的大量致病性病毒利用这种环境建立了慢性感染。效应T细胞和调节T细胞群，包括效应T细胞和驻留记忆T细胞，在介导急性感染向慢性感染的过渡中发挥着重要作用，在这一过程中，病毒复制在一定程度上是可以容忍的，以最大限度地减少免疫病理。慢性病毒感染期间持续的抗原暴露会导致这些反应的进化和分化。在这篇综述中，我们将讨论对慢性病毒感染期间粘膜 T 细胞免疫的认识进展，以及 T 细胞反应的特征是如何在粘膜的不同慢性病毒感染中发展的。我们认为对粘膜表面 T 细胞免疫的深入了解可为疫苗策略提供信息：不仅可以保护宿主免受慢性病毒感染，还可以利用可在粘膜表面持续存在的病毒作为疫苗载体。
{"title":"Mucosal T-cell responses to chronic viral infections: Implications for vaccine design","authors":"Mohammed Al-Talib, Sandra Dimonte, Ian R. Humphreys","doi":"10.1038/s41423-024-01140-2","DOIUrl":"10.1038/s41423-024-01140-2","url":null,"abstract":"Mucosal surfaces that line the respiratory, gastrointestinal and genitourinary tracts are the major interfaces between the immune system and the environment. Their unique immunological landscape is characterized by the necessity of balancing tolerance to commensal microorganisms and other innocuous exposures against protection from pathogenic threats such as viruses. Numerous pathogenic viruses, including herpesviruses and retroviruses, exploit this environment to establish chronic infection. Effector and regulatory T-cell populations, including effector and resident memory T cells, play instrumental roles in mediating the transition from acute to chronic infection, where a degree of viral replication is tolerated to minimize immunopathology. Persistent antigen exposure during chronic viral infection leads to the evolution and divergence of these responses. In this review, we discuss advances in the understanding of mucosal T-cell immunity during chronic viral infections and how features of T-cell responses develop in different chronic viral infections of the mucosa. We consider how insights into T-cell immunity at mucosal surfaces could inform vaccine strategies: not only to protect hosts from chronic viral infections but also to exploit viruses that can persist within mucosal surfaces as vaccine vectors.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 9","pages":"982-998"},"PeriodicalIF":21.8,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01140-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140064997","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 : 2024-03-06DOI: 10.1038/s41423-024-01142-0
Ronja Wieboldt, Michael Sandholzer, Emanuele Carlini, Chia-wei Lin, Anastasiya Börsch, Andreas Zingg, Didier Lardinois, Petra Herzig, Leyla Don, Alfred Zippelius, Heinz Läubli, Natalia Rodrigues Mantuano
The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells (MDSCs). We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated. In murine cancer models of emergency myelopoiesis, Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential. We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs. Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.
{"title":"Engagement of sialylated glycans with Siglec receptors on suppressive myeloid cells inhibits anticancer immunity via CCL2","authors":"Ronja Wieboldt, Michael Sandholzer, Emanuele Carlini, Chia-wei Lin, Anastasiya Börsch, Andreas Zingg, Didier Lardinois, Petra Herzig, Leyla Don, Alfred Zippelius, Heinz Läubli, Natalia Rodrigues Mantuano","doi":"10.1038/s41423-024-01142-0","DOIUrl":"10.1038/s41423-024-01142-0","url":null,"abstract":"The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells (MDSCs). We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated. In murine cancer models of emergency myelopoiesis, Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential. We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs. Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 5","pages":"495-509"},"PeriodicalIF":24.1,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01142-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048836","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 : 2024-03-05DOI: 10.1038/s41423-024-01144-y
Suiyi Tan, Wenjuan Li, Chan Yang, Qingping Zhan, Kunyu Lu, Jun Liu, Yong-Mei Jin, Jin-Song Bai, Lin Wang, Jinqing Li, Zhaofeng Li, Fei Yu, Yu-Ye Li, Yue-Xun Duan, Lu Lu, Tong Zhang, Jiaqi Wei, Lin Li, Yong-Tang Zheng, Shibo Jiang, Shuwen Liu
Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one β-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 β-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many β-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.
{"title":"gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity","authors":"Suiyi Tan, Wenjuan Li, Chan Yang, Qingping Zhan, Kunyu Lu, Jun Liu, Yong-Mei Jin, Jin-Song Bai, Lin Wang, Jinqing Li, Zhaofeng Li, Fei Yu, Yu-Ye Li, Yue-Xun Duan, Lu Lu, Tong Zhang, Jiaqi Wei, Lin Li, Yong-Tang Zheng, Shibo Jiang, Shuwen Liu","doi":"10.1038/s41423-024-01144-y","DOIUrl":"10.1038/s41423-024-01144-y","url":null,"abstract":"Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one β-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 β-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many β-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 5","pages":"479-494"},"PeriodicalIF":24.1,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038842","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 : 2024-03-05DOI: 10.1038/s41423-024-01145-x
Audrey Page, Nicolas Chuvin, Jenny Valladeau-Guilemond, Stéphane Depil
Natural killer (NK) cell-based immunotherapies are attracting increasing interest in the field of cancer treatment. Early clinical trials have shown promising outcomes, alongside satisfactory product efficacy and safety. Recent developments have greatly increased the therapeutic potential of NK cells by endowing them with enhanced recognition and cytotoxic capacities. This review focuses on surface receptor engineering in NK cell therapy and discusses its impact, challenges, and future directions. Most approaches are based on engineering with chimeric antigen receptors to allow NK cells to target specific tumor antigens independent of human leukocyte antigen restriction. This approach has increased the precision and potency of NK-mediated recognition and elimination of cancer cells. In addition, engineering NK cells with T-cell receptors also mediates the recognition of intracellular epitopes, which broadens the range of target peptides. Indirect tumor peptide recognition by NK cells has also been improved by optimizing immunoglobulin constant fragment receptor expression and signaling. Indeed, engineered NK cells have an improved ability to recognize and destroy target cells coated with specific antibodies, thereby increasing their antibody-dependent cellular cytotoxicity. The ability of NK cell receptor engineering to promote the expansion, persistence, and infiltration of transferred cells in the tumor microenvironment has also been explored. Receptor-based strategies for sustained NK cell functionality within the tumor environment have also been discussed, and these strategies providing perspectives to counteract tumor-induced immunosuppression. Overall, receptor engineering has led to significant advances in NK cell-based cancer immunotherapies. As technical challenges are addressed, these innovative treatments will likely reshape cancer immunotherapy.
基于自然杀伤（NK）细胞的免疫疗法在癌症治疗领域正引起越来越多的关注。早期的临床试验显示了良好的结果，以及令人满意的产品疗效和安全性。最近的发展赋予了 NK 细胞更强的识别和细胞毒性能力，从而大大提高了它们的治疗潜力。大多数方法都是基于嵌合抗原受体工程，使 NK 细胞不受人类白细胞抗原的限制，靶向特定的肿瘤抗原。这种方法提高了 NK 介导的识别和消灭癌细胞的精确度和效力。此外，带有 T 细胞受体的 NK 细胞还能识别细胞内表位，从而扩大了靶肽的范围。通过优化免疫球蛋白常量片段受体的表达和信号传导，NK 细胞对肿瘤多肽的间接识别能力也得到了提高。事实上，经过改造的 NK 细胞具有更强的识别和摧毁涂有特异性抗体的靶细胞的能力，从而提高了其抗体依赖性细胞毒性。人们还探索了 NK 细胞受体工程在肿瘤微环境中促进转移细胞的扩增、持续存在和浸润的能力。此外，还讨论了基于受体的在肿瘤环境中维持 NK 细胞功能的策略，这些策略为对抗肿瘤诱导的免疫抑制提供了前景。随着技术挑战的解决，这些创新疗法很可能会重塑癌症免疫疗法。
{"title":"Development of NK cell-based cancer immunotherapies through receptor engineering","authors":"Audrey Page, Nicolas Chuvin, Jenny Valladeau-Guilemond, Stéphane Depil","doi":"10.1038/s41423-024-01145-x","DOIUrl":"10.1038/s41423-024-01145-x","url":null,"abstract":"Natural killer (NK) cell-based immunotherapies are attracting increasing interest in the field of cancer treatment. Early clinical trials have shown promising outcomes, alongside satisfactory product efficacy and safety. Recent developments have greatly increased the therapeutic potential of NK cells by endowing them with enhanced recognition and cytotoxic capacities. This review focuses on surface receptor engineering in NK cell therapy and discusses its impact, challenges, and future directions. Most approaches are based on engineering with chimeric antigen receptors to allow NK cells to target specific tumor antigens independent of human leukocyte antigen restriction. This approach has increased the precision and potency of NK-mediated recognition and elimination of cancer cells. In addition, engineering NK cells with T-cell receptors also mediates the recognition of intracellular epitopes, which broadens the range of target peptides. Indirect tumor peptide recognition by NK cells has also been improved by optimizing immunoglobulin constant fragment receptor expression and signaling. Indeed, engineered NK cells have an improved ability to recognize and destroy target cells coated with specific antibodies, thereby increasing their antibody-dependent cellular cytotoxicity. The ability of NK cell receptor engineering to promote the expansion, persistence, and infiltration of transferred cells in the tumor microenvironment has also been explored. Receptor-based strategies for sustained NK cell functionality within the tumor environment have also been discussed, and these strategies providing perspectives to counteract tumor-induced immunosuppression. Overall, receptor engineering has led to significant advances in NK cell-based cancer immunotherapies. As technical challenges are addressed, these innovative treatments will likely reshape cancer immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 4","pages":"315-331"},"PeriodicalIF":24.1,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01145-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038841","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 : 2024-03-01DOI: 10.1038/s41423-024-01126-0
Sujin Lee, Yeunjung Ko, Hyun Woo Lee, Won Joon Oh, Hun Gi Hong, Dinuka Ariyaratne, Se Jin Im, Tae Jin Kim
Marginal zone (MZ) B cells, which are splenic innate-like B cells that rapidly secrete antibodies (Abs) against blood-borne pathogens, are composed of heterogeneous subpopulations. Here, we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels. CD80high MZ B cells exhibited greater Ab-producing, proliferative, and IL-10-secreting capacities than did CD80low MZ B cells. Notably, CD80high MZ B cells survived 2-Gy whole-body irradiation, whereas CD80low MZ B cells were depleted by irradiation and then repleted with one month after irradiation. Depletion of CD80low MZ B cells led to accelerated development of type II collagen (CII)-induced arthritis upon immunization with bovine CII. CD80high MZ B cells exhibited higher expression of genes involved in proliferation, plasma cell differentiation, and the antioxidant response. CD80high MZ B cells expressed more autoreactive B cell receptors (BCRs) that recognized double-stranded DNA or CII, expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences, and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80low MZ B cells. Adoptive transfer experiments showed that CD21+CD23+ transitional 2 MZ precursors preferentially generated CD80low MZ B cells and that a proportion of CD80low MZ B cells were converted into CD80high MZ B cells; in contrast, CD80high MZ B cells stably remained CD80high MZ B cells. In summary, MZ B cells can be divided into two subpopulations according to their CD80 expression levels, Ab-producing capacity, radioresistance, and autoreactivity, and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.
边缘区（MZ）B细胞是脾脏先天性B细胞，能快速分泌抗体（Abs）对抗血源性病原体，它由不同的亚群组成。在这里，我们发现 MZ B 细胞可根据其 CD80 表达水平分为两个不同的亚群。与 CD80 低的 MZ B 细胞相比，CD80 高的 MZ B 细胞具有更强的抗体生成、增殖和 IL-10 分泌能力。值得注意的是，CD80高的MZ B细胞能在2-Gy全身辐照后存活，而CD80低的MZ B细胞则会因辐照而耗竭，并在辐照一个月后重新耗竭。CD80低MZ B细胞的耗竭导致牛CII免疫后II型胶原蛋白（CII）诱导的关节炎加速发展。CD80 高的 MZ B 细胞在涉及增殖、浆细胞分化和抗氧化反应的基因中表现出更高的表达量。与 CD80 低的 MZ B 细胞相比，CD80 高的 MZ B 细胞表达更多识别双链 DNA 或 CII 的自反应性 B 细胞受体（BCR），表达更多具有较短互补决定区 3 序列的免疫球蛋白重链序列，并包含更多无 N 核苷酸或具有 B-1a BCR 序列的克隆型。采用性转移实验表明，CD21+CD23+过渡性2 MZ前体优先生成CD80低MZ B细胞，一部分CD80低MZ B细胞转化为CD80高MZ B细胞；相比之下，CD80高MZ B细胞稳定地保持为CD80高MZ B细胞。总之，MZ B细胞可根据其CD80表达水平、Ab生成能力、放射抗性和自反应性分为两个亚群，这些发现可能表明MZ B细胞的组成是分层的，具有不同的稳定性和BCR特异性。
{"title":"Two distinct subpopulations of marginal zone B cells exhibit differential antibody-producing capacities and radioresistance","authors":"Sujin Lee, Yeunjung Ko, Hyun Woo Lee, Won Joon Oh, Hun Gi Hong, Dinuka Ariyaratne, Se Jin Im, Tae Jin Kim","doi":"10.1038/s41423-024-01126-0","DOIUrl":"10.1038/s41423-024-01126-0","url":null,"abstract":"Marginal zone (MZ) B cells, which are splenic innate-like B cells that rapidly secrete antibodies (Abs) against blood-borne pathogens, are composed of heterogeneous subpopulations. Here, we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels. CD80high MZ B cells exhibited greater Ab-producing, proliferative, and IL-10-secreting capacities than did CD80low MZ B cells. Notably, CD80high MZ B cells survived 2-Gy whole-body irradiation, whereas CD80low MZ B cells were depleted by irradiation and then repleted with one month after irradiation. Depletion of CD80low MZ B cells led to accelerated development of type II collagen (CII)-induced arthritis upon immunization with bovine CII. CD80high MZ B cells exhibited higher expression of genes involved in proliferation, plasma cell differentiation, and the antioxidant response. CD80high MZ B cells expressed more autoreactive B cell receptors (BCRs) that recognized double-stranded DNA or CII, expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences, and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80low MZ B cells. Adoptive transfer experiments showed that CD21+CD23+ transitional 2 MZ precursors preferentially generated CD80low MZ B cells and that a proportion of CD80low MZ B cells were converted into CD80high MZ B cells; in contrast, CD80high MZ B cells stably remained CD80high MZ B cells. In summary, MZ B cells can be divided into two subpopulations according to their CD80 expression levels, Ab-producing capacity, radioresistance, and autoreactivity, and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 4","pages":"393-408"},"PeriodicalIF":24.1,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995754","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 : 2024-02-27DOI: 10.1038/s41423-024-01134-0
Zhengnan Cai, Wan Li, Sonja Hager, Jayne Louise Wilson, Leila Afjehi-Sadat, Elke H. Heiss, Thomas Weichhart, Petra Heffeter, Wolfram Weckwerth
Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) is poorly understood. Here, we found that the T helper 2 (Th2) cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration, which are essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment. Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs toward an M1-like phenotype, downregulated PD-L1 expression and enhanced antitumor T-cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.
磷酸甘油脱氢酶（PHGDH）已成为癌细胞、淋巴细胞和内皮细胞合成大分子、中和氧化应激以及调节甲基化反应的关键因素。然而，人们对 PHGDH 在肿瘤相关巨噬细胞（TAMs）中的作用知之甚少。在这里，我们发现T辅助2（Th2）细胞因子白细胞介素-4和肿瘤调节介质会上调巨噬细胞中PHGDH的表达，并促进免疫抑制性M2巨噬细胞的活化和增殖。PHGDH 的缺失会破坏细胞代谢和线粒体呼吸，而这对于免疫抑制巨噬细胞来说是必不可少的。从机理上讲，PHGDH 介导的丝氨酸生物合成促进了 α-酮戊二酸的产生，从而激活了 mTORC1 信号传导，有助于在肿瘤微环境中维持 M2 样巨噬细胞表型。遗传性消减肿瘤小鼠巨噬细胞中的 PHGDH 会导致肿瘤生长减慢、TAM 浸润减少、M2 样 TAM 表型向 M1 样表型转变、PD-L1 表达下调以及抗肿瘤 T 细胞免疫增强。我们的研究为进一步探索 PHGDH 作为潜在靶点以对抗 TAM 介导的免疫抑制和阻碍肿瘤进展提供了坚实的基础。
{"title":"Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling","authors":"Zhengnan Cai, Wan Li, Sonja Hager, Jayne Louise Wilson, Leila Afjehi-Sadat, Elke H. Heiss, Thomas Weichhart, Petra Heffeter, Wolfram Weckwerth","doi":"10.1038/s41423-024-01134-0","DOIUrl":"10.1038/s41423-024-01134-0","url":null,"abstract":"Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) is poorly understood. Here, we found that the T helper 2 (Th2) cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration, which are essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment. Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs toward an M1-like phenotype, downregulated PD-L1 expression and enhanced antitumor T-cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 5","pages":"448-465"},"PeriodicalIF":24.1,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01134-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971112","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 : 2024-02-26DOI: 10.1038/s41423-024-01137-x
Hyo Jeong Kim, Yun Sang Lee, Bok-Soon Lee, Chang-Hak Han, Sang Gyu Kim, Chul-Ho Kim
Inflammasomes are multiprotein complexes involved in the host immune response to pathogen infections. Thus, inflammasomes participate in many conditions, such as acne. Recently, it was shown that NETosis, a type of neutrophil cell death, is induced by bacterial infection and is involved in inflammatory diseases such as delayed wound healing in patients with diabetes. However, the relationship between inflammasomes and NETosis in the pathogenesis of inflammatory diseases has not been well studied. In this study, we determined whether NETosis is induced in P. acnes-induced skin inflammation and whether activation of the nucleotide-binding domain, leucine-rich family, and pyrin domain-containing-3 (NLRP3) inflammasome is one of the key factors involved in NETosis induction in a mouse model of acne skin inflammation. We found that NETosis was induced in P. acnes-induced skin inflammation in mice and that inhibition of NETosis ameliorated P. acnes-induced skin inflammation. In addition, our results demonstrated that inhibiting inflammasome activation could suppress NETosis induction in mouse skin. These results indicate that inflammasomes and NETosis can interact with each other to induce P. acnes-induced skin inflammation and suggest that targeting NETosis could be a potential treatment for inflammasome-mediated diseases as well as NETosis-related diseases.
{"title":"NLRP3 inflammasome activation and NETosis positively regulate each other and exacerbate proinflammatory responses: implications of NETosis inhibition for acne skin inflammation treatment","authors":"Hyo Jeong Kim, Yun Sang Lee, Bok-Soon Lee, Chang-Hak Han, Sang Gyu Kim, Chul-Ho Kim","doi":"10.1038/s41423-024-01137-x","DOIUrl":"10.1038/s41423-024-01137-x","url":null,"abstract":"Inflammasomes are multiprotein complexes involved in the host immune response to pathogen infections. Thus, inflammasomes participate in many conditions, such as acne. Recently, it was shown that NETosis, a type of neutrophil cell death, is induced by bacterial infection and is involved in inflammatory diseases such as delayed wound healing in patients with diabetes. However, the relationship between inflammasomes and NETosis in the pathogenesis of inflammatory diseases has not been well studied. In this study, we determined whether NETosis is induced in P. acnes-induced skin inflammation and whether activation of the nucleotide-binding domain, leucine-rich family, and pyrin domain-containing-3 (NLRP3) inflammasome is one of the key factors involved in NETosis induction in a mouse model of acne skin inflammation. We found that NETosis was induced in P. acnes-induced skin inflammation in mice and that inhibition of NETosis ameliorated P. acnes-induced skin inflammation. In addition, our results demonstrated that inhibiting inflammasome activation could suppress NETosis induction in mouse skin. These results indicate that inflammasomes and NETosis can interact with each other to induce P. acnes-induced skin inflammation and suggest that targeting NETosis could be a potential treatment for inflammasome-mediated diseases as well as NETosis-related diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 5","pages":"466-478"},"PeriodicalIF":24.1,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139968449","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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