Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.
{"title":"Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma.","authors":"Yongchun Wang, Weibai Chen, Shuang Qiao, Hao Zou, Xing-Juan Yu, Yanyan Yang, Zhixiong Li, Junfeng Wang, Min-Shan Chen, Jing Xu, Limin Zheng","doi":"10.1038/s41423-024-01199-x","DOIUrl":"https://doi.org/10.1038/s41423-024-01199-x","url":null,"abstract":"<p><p>Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8<sup>+</sup> T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6<sup>+</sup> Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466539","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 : 2024-06-28DOI: 10.1038/s41423-024-01195-1
Bilal Alashkar Alhamwe, Viviane Ponath, Fahd Alhamdan, Bastian Dörsam, Clara Landwehr, Manuel Linder, Kim Pauck, Sarah Miethe, Holger Garn, Florian Finkernagel, Anna Brichkina, Matthias Lauth, Dinesh Kumar Tiwari, Malte Buchholz, Daniel Bachurski, Sabrina Elmshäuser, Andrea Nist, Thorsten Stiewe, Lisa Pogge von Strandmann, Witold Szymański, Vanessa Beutgen, Johannes Graumann, Julia Teply-Szymanski, Corinna Keber, Carsten Denkert, Ralf Jacob, Christian Preußer, Elke Pogge von Strandmann
Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.
最近的研究表明，肿瘤细胞释放的细胞外囊泡（EV）在胰腺癌（PC）进展中起着关键作用。然而，指导 EV 功能的驱动基因、EV 接收细胞及其对 EV 吸收的细胞反应仍有待确定。因此，我们研究了 Bcl-2-associated-anthanogene 6（BAG6）在癌症进展中的作用，它是 EV 生物发生的调控因子。我们使用基于 Cre 重组酶/LoxP 的报告系统，结合单细胞 RNA 测序，在 Bag6 亲合或缺乏背景的胰腺导管腺癌（PDAC）小鼠模型中监测体内 EV 摄取和肿瘤微环境（TME）变化。使用小鼠和人类器官组织以及患者样本对体内数据进行了验证。我们的数据表明，Bag6缺陷的皮下和正位PDAC肿瘤依赖于EV的释放而加速肿瘤生长。从机理上讲，这是由于肥大细胞（MC）通过EV相关的IL33被激活。活化的肥大细胞促进了肿瘤细胞的增殖，并改变了TME的组成，影响了成纤维细胞的极化和免疫细胞的浸润。肿瘤细胞增殖和成纤维细胞极化是通过含有高水平PDGF和CD73的MC分泌组介导的。高BAG6基因表达和高蛋白血浆水平的患者总生存期更长，这表明该研究具有临床意义。目前的研究揭示了 BAG6 在 PDAC 中迄今未知的肿瘤抑制活性。Bag6缺失会导致EV相关的IL33释放，而IL33会通过激活MC调节TME，促进肿瘤的侵袭性生长。使用伊马替尼清除MC可减少肿瘤生长，这为考虑对BAG6低表达和MC高浸润的患者使用伊马替尼提供了科学依据。从BAG6缺陷的胰腺癌细胞中提取的EV通过IL33/Il1rl1诱导MC活化。活化的MC的分泌物诱导肿瘤增殖和TME变化，尤其是使成纤维细胞转变为炎症性癌症相关成纤维细胞（iCAF）表型。阻断EVs或消耗MCs可限制肿瘤生长。
{"title":"BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells","authors":"Bilal Alashkar Alhamwe, Viviane Ponath, Fahd Alhamdan, Bastian Dörsam, Clara Landwehr, Manuel Linder, Kim Pauck, Sarah Miethe, Holger Garn, Florian Finkernagel, Anna Brichkina, Matthias Lauth, Dinesh Kumar Tiwari, Malte Buchholz, Daniel Bachurski, Sabrina Elmshäuser, Andrea Nist, Thorsten Stiewe, Lisa Pogge von Strandmann, Witold Szymański, Vanessa Beutgen, Johannes Graumann, Julia Teply-Szymanski, Corinna Keber, Carsten Denkert, Ralf Jacob, Christian Preußer, Elke Pogge von Strandmann","doi":"10.1038/s41423-024-01195-1","DOIUrl":"10.1038/s41423-024-01195-1","url":null,"abstract":"Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466515","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 : 2024-06-27DOI: 10.1038/s41423-024-01198-y
Zhangqi Dou, Thomas Raphael Bonacci, Peishun Shou, Elisa Landoni, Mark G. Woodcock, Chuang Sun, Barbara Savoldo, Laura E. Herring, Michael J. Emanuele, Feifei Song, Albert S. Baldwin, Yisong Wan, Gianpietro Dotti, Xin Zhou
CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling. Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity, cell aggregation via ICAM-1 overexpression, and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway. Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.
{"title":"4-1BB-encoding CAR causes cell death via sequestration of the ubiquitin-modifying enzyme A20","authors":"Zhangqi Dou, Thomas Raphael Bonacci, Peishun Shou, Elisa Landoni, Mark G. Woodcock, Chuang Sun, Barbara Savoldo, Laura E. Herring, Michael J. Emanuele, Feifei Song, Albert S. Baldwin, Yisong Wan, Gianpietro Dotti, Xin Zhou","doi":"10.1038/s41423-024-01198-y","DOIUrl":"10.1038/s41423-024-01198-y","url":null,"abstract":"CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling. Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity, cell aggregation via ICAM-1 overexpression, and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway. Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466514","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 : 2024-06-25DOI: 10.1038/s41423-024-01189-z
Yunhui Niu, Marjolein Heddes, Baraa Altaha, Michael Birkner, Karin Kleigrewe, Chen Meng, Dirk Haller, Silke Kiessling
The expression of clock genes has been observed to be impaired in biopsies from patients with inflammatory bowel disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The peripheral circadian clock in intestinal epithelial cells (IECs) was previously shown to balance gastrointestinal homeostasis by regulating the microbiome. Here, we demonstrated that the intestinal clock is disrupted in an IBD-relevant mouse model (IL-10−/−). A lack of the intestinal clock gene (Bmal1) in intestinal epithelial cells (IECs) in a chemically and a novel genetically induced colitis model (DSS, Bmal1IEC−/−xIL-10−/−) promoted colitis and dramatically reduced survival rates. Germ-free Bmal1IEC−/− mice colonized with disease-associated microbiota from IL-10−/− mice exhibited increased inflammatory responses, highlighting the importance of the local intestinal clock for microbiota-induced IBD development. Targeting the intestinal clock directly by timed restricted feeding (RF) in IL-10−/− mice restored intestinal clock functions, including immune cell recruitment and microbial rhythmicity; improved inflammatory responses; dramatically enhanced survival rates and rescued the histopathological phenotype. In contrast, RF failed to improve IBD symptoms in Bmal1IEC−/−xIL-10−/− mice, demonstrating the significance of the intestinal clock in determining the beneficial effect of RF. Overall, we provide evidence that intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis. Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate symptoms in IBD patients.
{"title":"Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation","authors":"Yunhui Niu, Marjolein Heddes, Baraa Altaha, Michael Birkner, Karin Kleigrewe, Chen Meng, Dirk Haller, Silke Kiessling","doi":"10.1038/s41423-024-01189-z","DOIUrl":"10.1038/s41423-024-01189-z","url":null,"abstract":"The expression of clock genes has been observed to be impaired in biopsies from patients with inflammatory bowel disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The peripheral circadian clock in intestinal epithelial cells (IECs) was previously shown to balance gastrointestinal homeostasis by regulating the microbiome. Here, we demonstrated that the intestinal clock is disrupted in an IBD-relevant mouse model (IL-10−/−). A lack of the intestinal clock gene (Bmal1) in intestinal epithelial cells (IECs) in a chemically and a novel genetically induced colitis model (DSS, Bmal1IEC−/−xIL-10−/−) promoted colitis and dramatically reduced survival rates. Germ-free Bmal1IEC−/− mice colonized with disease-associated microbiota from IL-10−/− mice exhibited increased inflammatory responses, highlighting the importance of the local intestinal clock for microbiota-induced IBD development. Targeting the intestinal clock directly by timed restricted feeding (RF) in IL-10−/− mice restored intestinal clock functions, including immune cell recruitment and microbial rhythmicity; improved inflammatory responses; dramatically enhanced survival rates and rescued the histopathological phenotype. In contrast, RF failed to improve IBD symptoms in Bmal1IEC−/−xIL-10−/− mice, demonstrating the significance of the intestinal clock in determining the beneficial effect of RF. Overall, we provide evidence that intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis. Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate symptoms in IBD patients.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449846","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 : 2024-06-25DOI: 10.1038/s41423-024-01188-0
Carolina R. Melo-Silva, Luis J. Sigal
The interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. Regardless of the entry mechanism, infected myeloid antigen-presenting cells, including various subtypes of dendritic cells, inflammatory monocytes, and macrophages, play a critical role in initiating the innate immune response within the dLN. This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons (IFN-Is) and other cytokines and recruit inflammatory monocytes and natural killer (NK) cells. IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease. Additionally, the memory CD8+ T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections. This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+ T-cells following secondary infection or CD8+ T-cell vaccination.
组织间隙液不断通过传入淋巴管以淋巴形式排入淋巴结（LN），并通过传出淋巴管从淋巴结进入血液。淋巴结位置优越，具有适当的细胞组成，可作为对抗入侵病原体的适应性免疫起始点。然而，对于通过淋巴系统从进入部位扩散到其他组织的淋巴传播病毒来说，引流淋巴结（dLN）中的免疫细胞在原发性和继发性感染期间也在遏制全身性病毒传播方面发挥着关键作用。组织中的淋巴传播病毒可作为淋巴中的游离病毒或感染细胞内的病毒被运送到引流淋巴结。无论是哪种进入机制，受感染的骨髓抗原递呈细胞，包括各种亚型的树突状细胞、炎性单核细胞和巨噬细胞，都在启动 dLN 内的先天性免疫反应中发挥着关键作用。这种先天性免疫反应涉及受感染的先天性免疫细胞和旁观者先天性免疫细胞之间的细胞串联，最终产生 I 型干扰素（IFN-Is）和其他细胞因子，并招募炎性单核细胞和自然杀伤细胞（NK）。IFN-I 和 NK 细胞的细胞毒性可在原发性感染期间限制病毒的全身扩散，防止严重疾病的发生。此外，驻留或快速迁移到 dLN 的记忆 CD8+ T 细胞也有助于在继发性病毒感染时预防疾病。这篇综述探讨了包含原发性病毒感染的 dLN 内错综复杂的先天性免疫反应，以及记忆 CD8+ T 细胞在继发性感染或 CD8+ T 细胞疫苗接种后的作用。
{"title":"Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node","authors":"Carolina R. Melo-Silva, Luis J. Sigal","doi":"10.1038/s41423-024-01188-0","DOIUrl":"10.1038/s41423-024-01188-0","url":null,"abstract":"The interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. Regardless of the entry mechanism, infected myeloid antigen-presenting cells, including various subtypes of dendritic cells, inflammatory monocytes, and macrophages, play a critical role in initiating the innate immune response within the dLN. This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons (IFN-Is) and other cytokines and recruit inflammatory monocytes and natural killer (NK) cells. IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease. Additionally, the memory CD8+ T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections. This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+ T-cells following secondary infection or CD8+ T-cell vaccination.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01188-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449845","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 : 2024-06-21DOI: 10.1038/s41423-024-01193-3
Jing Guo, Hui Zheng, Sidong Xiong
Type I interferon (IFN-I) exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections. In this study, we unveil SENP6 as a potent regulator of IFN-I antiviral activity. SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling. Mechanistically, SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8, consequently restricting the interaction between USP8 and IFNAR2. The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation, thus attenuating IFN-I antiviral activity. Correspondingly, the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2, leading to a reduction in IFNAR2 ubiquitination and, consequently, an enhancement in IFN-I-induced signaling. This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.
{"title":"SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8","authors":"Jing Guo, Hui Zheng, Sidong Xiong","doi":"10.1038/s41423-024-01193-3","DOIUrl":"10.1038/s41423-024-01193-3","url":null,"abstract":"Type I interferon (IFN-I) exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections. In this study, we unveil SENP6 as a potent regulator of IFN-I antiviral activity. SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling. Mechanistically, SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8, consequently restricting the interaction between USP8 and IFNAR2. The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation, thus attenuating IFN-I antiviral activity. Correspondingly, the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2, leading to a reduction in IFNAR2 ubiquitination and, consequently, an enhancement in IFN-I-induced signaling. This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436409","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 : 2024-06-20DOI: 10.1038/s41423-024-01187-1
Saeed Daneshmandi, Qi Yan, Jee Eun Choi, Eriko Katsuta, Cameron R. MacDonald, Mounika Goruganthu, Nathan Roberts, Elizabeth A. Repasky, Prashant K. Singh, Kristopher Attwood, Jianmin Wang, Yosef Landesman, Philip L. McCarthy, Hemn Mohammadpour
Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.
{"title":"Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export","authors":"Saeed Daneshmandi, Qi Yan, Jee Eun Choi, Eriko Katsuta, Cameron R. MacDonald, Mounika Goruganthu, Nathan Roberts, Elizabeth A. Repasky, Prashant K. Singh, Kristopher Attwood, Jianmin Wang, Yosef Landesman, Philip L. McCarthy, Hemn Mohammadpour","doi":"10.1038/s41423-024-01187-1","DOIUrl":"10.1038/s41423-024-01187-1","url":null,"abstract":"Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431557","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 : 2024-06-13DOI: 10.1038/s41423-024-01190-6
Qing Ouyang, Chao Wang, Tian Sang, Yan Tong, Jian Zhang, Yulan Chen, Xue Wang, Lingling Wu, Xu Wang, Ran Liu, Pu Chen, Jiaona Liu, Wanjun Shen, Zhe Feng, Li Zhang, Xuefeng Sun, Guangyan Cai, Li-Li Li, Xiangmei Chen
Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys. Renal fibrosis involves an immune response dominated by macrophages, which activates myofibroblasts in fibrotic niches. However, macrophages exhibit high heterogeneity, hindering their potential as therapeutic cell targets. Herein, we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially. We identified the major profibrotic macrophage subset (Fn1+Spp1+Arg1+) in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK (BIVA-PK) to deplete these cells. BIVA-PK specifically binds to and is internalized by profibrotic macrophages. By inducing macrophage cell death, BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses. The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.
{"title":"Depleting profibrotic macrophages using bioactivated in vivo assembly peptides ameliorates kidney fibrosis","authors":"Qing Ouyang, Chao Wang, Tian Sang, Yan Tong, Jian Zhang, Yulan Chen, Xue Wang, Lingling Wu, Xu Wang, Ran Liu, Pu Chen, Jiaona Liu, Wanjun Shen, Zhe Feng, Li Zhang, Xuefeng Sun, Guangyan Cai, Li-Li Li, Xiangmei Chen","doi":"10.1038/s41423-024-01190-6","DOIUrl":"10.1038/s41423-024-01190-6","url":null,"abstract":"Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys. Renal fibrosis involves an immune response dominated by macrophages, which activates myofibroblasts in fibrotic niches. However, macrophages exhibit high heterogeneity, hindering their potential as therapeutic cell targets. Herein, we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially. We identified the major profibrotic macrophage subset (Fn1+Spp1+Arg1+) in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK (BIVA-PK) to deplete these cells. BIVA-PK specifically binds to and is internalized by profibrotic macrophages. By inducing macrophage cell death, BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses. The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316850","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}
The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.
{"title":"Chaperone- and PTM-mediated activation of IRF1 tames radiation-induced cell death and the inflammatory response","authors":"Fenghao Geng, Jianhui Chen, Bin Song, Zhicheng Tang, Xiaoqian Li, Shuaijun Zhang, Tingyi Yang, Yulan Liu, Wei Mo, Yining Zhang, Chuntang Sun, Lei Tan, Wenling Tu, Daojiang Yu, Jianping Cao, Shuyu Zhang","doi":"10.1038/s41423-024-01185-3","DOIUrl":"10.1038/s41423-024-01185-3","url":null,"abstract":"The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287824","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 : 2024-06-05DOI: 10.1038/s41423-024-01183-5
Akihiro Nakamura, Sungsin Jo, Sayaka Nakamura, Mansi K. Aparnathi, Shaghayegh Foroozan Boroojeni, Mariia Korshko, Ye-Soo Park, Himanshi Gupta, Sandra Vijayan, Jason S. Rockel, Mohit Kapoor, Igor Jurisica, Tae-Hwan Kim, Nigil Haroon
The hallmarks of spondyloarthritis (SpA) are type 3 immunity-driven inflammation and new bone formation (NBF). Macrophage migration inhibitory factor (MIF) was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity, yet MIF-interacting molecules and networks remain elusive. Herein, we identified hypoxia-inducible factor-1 alpha (HIF1A) as an interacting partner molecule of MIF that drives SpA pathologies, including inflammation and NBF. HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG (curdlan-SKG) mice compared to the respective controls. Under hypoxic conditions in which HIF1A was stabilized, human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23, an upstream type 3 immunity-related cytokine. Similar to MIF, systemic overexpression of IL-23 induced SpA pathology in SKG mice, while the injection of a HIF1A-selective inhibitor (PX-478) into curdlan-SKG mice prevented or attenuated SpA pathology, as indicated by a marked reduction in the expression of MIF and IL-23. Furthermore, genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF, despite the presence of psoriasis-like dermatitis and blepharitis. We also found that MIF- and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice. These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification. Together, these results provide supporting evidence for an MIF/HIF1A regulatory network, and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.
{"title":"HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model","authors":"Akihiro Nakamura, Sungsin Jo, Sayaka Nakamura, Mansi K. Aparnathi, Shaghayegh Foroozan Boroojeni, Mariia Korshko, Ye-Soo Park, Himanshi Gupta, Sandra Vijayan, Jason S. Rockel, Mohit Kapoor, Igor Jurisica, Tae-Hwan Kim, Nigil Haroon","doi":"10.1038/s41423-024-01183-5","DOIUrl":"10.1038/s41423-024-01183-5","url":null,"abstract":"The hallmarks of spondyloarthritis (SpA) are type 3 immunity-driven inflammation and new bone formation (NBF). Macrophage migration inhibitory factor (MIF) was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity, yet MIF-interacting molecules and networks remain elusive. Herein, we identified hypoxia-inducible factor-1 alpha (HIF1A) as an interacting partner molecule of MIF that drives SpA pathologies, including inflammation and NBF. HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG (curdlan-SKG) mice compared to the respective controls. Under hypoxic conditions in which HIF1A was stabilized, human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23, an upstream type 3 immunity-related cytokine. Similar to MIF, systemic overexpression of IL-23 induced SpA pathology in SKG mice, while the injection of a HIF1A-selective inhibitor (PX-478) into curdlan-SKG mice prevented or attenuated SpA pathology, as indicated by a marked reduction in the expression of MIF and IL-23. Furthermore, genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF, despite the presence of psoriasis-like dermatitis and blepharitis. We also found that MIF- and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice. These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification. Together, these results provide supporting evidence for an MIF/HIF1A regulatory network, and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141255495","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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