Pub Date : 2024-06-05DOI: 10.1038/s41423-024-01180-8
Mario Ruiz Pérez, Christian Maueröder, Wolf Steels, Bruno Verstraeten, Sahine Lameire, Wei Xie, Laura Wyckaert, Jelle Huysentruyt, Tatyana Divert, Ria Roelandt, Amanda Gonçalves, Riet De Rycke, Kodi Ravichandran, Bart N. Lambrecht, Tom Taghon, Georges Leclercq, Peter Vandenabeele, Peter Tougaard
Acute systemic inflammation critically alters the function of the immune system, often promoting myelopoiesis at the expense of lymphopoiesis. In the thymus, systemic inflammation results in acute thymic atrophy and, consequently, impaired T-lymphopoiesis. The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear. Here, we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis. The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced acute thymic atrophy, while thymic neutrophils expanded. Fate mapping with Ms4a3-Cre mice demonstrated that thymic neutrophils emerge from thymic granulocyte-monocyte progenitors (GMPs), while Rag1-Cre fate mapping revealed a common developmental path with lymphocytes. These effects could be modeled ex vivo using neonatal thymic organ cultures (NTOCs), where TL1A and IL-18 synergistically enhanced neutrophil production and egress. NOTCH blockade by the LY411575 inhibitor increased the number of neutrophils in the culture, indicating that NOTCH restricted steady-state thymic granulopoiesis. To promote myelopoiesis, TL1A, and IL-18 synergistically increased GM-CSF levels in the NTOC, which was mainly produced by thymic ILC1s. In support, TL1A- and IL-18-induced granulopoiesis was completely prevented in NTOCs derived from Csf2rb-/- mice and by GM-CSFR antibody blockade, revealing that GM-CSF is the essential factor driving thymic granulopoiesis. Taken together, our findings reveal that TL1A and IL-18 synergism induce acute thymus atrophy while promoting extramedullary thymic granulopoiesis in a NOTCH and GM-CSF-controlled manner.
急性全身性炎症会严重改变免疫系统的功能，通常会促进骨髓造血，而牺牲淋巴造血。在胸腺中，全身性炎症会导致急性胸腺萎缩，从而损害 T 淋巴细胞的生成。除了抑制 T 细胞发育外，全身性炎症影响胸腺的机制仍不清楚。在这里，我们描述了TL1A和IL-18如何协同抑制T淋巴细胞生成以促进胸腺骨髓细胞生成。在病毒诱导的胸腺萎缩感染小鼠巨细胞病毒（MCMV）或小鼠肺炎病毒（PVM）期间，胸腺中这两种细胞因子的蛋白水平升高。体内注射TL1A和IL-18会诱发急性胸腺萎缩，同时胸腺中性粒细胞会增大。用Ms4a3-Cre小鼠绘制的命运图谱显示，胸腺中性粒细胞是从胸腺粒细胞-单核细胞祖细胞（GMPs）中产生的，而Rag1-Cre命运图谱则显示了与淋巴细胞共同的发育路径。这些效应可通过新生儿胸腺器官培养物（NTOCs）进行体内外模拟，其中TL1A和IL-18协同增强了中性粒细胞的产生和排出。LY411575抑制剂阻断NOTCH可增加培养物中中性粒细胞的数量，这表明NOTCH限制了稳态胸腺粒细胞生成。为促进骨髓造血，TL1A 和 IL-18 协同提高了 NTOC 中 GM-CSF 的水平，而 GM-CSF 主要由胸腺 ILC1s 产生。此外，TL1A和IL-18诱导的粒细胞生成在Csf2rb-/-小鼠的NTOC中和GM-CSFR抗体阻断后完全被阻止，这表明GM-CSF是驱动胸腺粒细胞生成的重要因子。综上所述，我们的研究结果表明，TL1A和IL-18协同诱导急性胸腺萎缩，同时以NOTCH和GM-CSF控制的方式促进髓外胸腺造粒。
{"title":"TL1A and IL-18 synergy promotes GM-CSF-dependent thymic granulopoiesis in mice","authors":"Mario Ruiz Pérez, Christian Maueröder, Wolf Steels, Bruno Verstraeten, Sahine Lameire, Wei Xie, Laura Wyckaert, Jelle Huysentruyt, Tatyana Divert, Ria Roelandt, Amanda Gonçalves, Riet De Rycke, Kodi Ravichandran, Bart N. Lambrecht, Tom Taghon, Georges Leclercq, Peter Vandenabeele, Peter Tougaard","doi":"10.1038/s41423-024-01180-8","DOIUrl":"10.1038/s41423-024-01180-8","url":null,"abstract":"Acute systemic inflammation critically alters the function of the immune system, often promoting myelopoiesis at the expense of lymphopoiesis. In the thymus, systemic inflammation results in acute thymic atrophy and, consequently, impaired T-lymphopoiesis. The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear. Here, we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis. The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced acute thymic atrophy, while thymic neutrophils expanded. Fate mapping with Ms4a3-Cre mice demonstrated that thymic neutrophils emerge from thymic granulocyte-monocyte progenitors (GMPs), while Rag1-Cre fate mapping revealed a common developmental path with lymphocytes. These effects could be modeled ex vivo using neonatal thymic organ cultures (NTOCs), where TL1A and IL-18 synergistically enhanced neutrophil production and egress. NOTCH blockade by the LY411575 inhibitor increased the number of neutrophils in the culture, indicating that NOTCH restricted steady-state thymic granulopoiesis. To promote myelopoiesis, TL1A, and IL-18 synergistically increased GM-CSF levels in the NTOC, which was mainly produced by thymic ILC1s. In support, TL1A- and IL-18-induced granulopoiesis was completely prevented in NTOCs derived from Csf2rb-/- mice and by GM-CSFR antibody blockade, revealing that GM-CSF is the essential factor driving thymic granulopoiesis. Taken together, our findings reveal that TL1A and IL-18 synergism induce acute thymus atrophy while promoting extramedullary thymic granulopoiesis in a NOTCH and GM-CSF-controlled manner.","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":"https://www.nature.com/articles/s41423-024-01180-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141255646","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 : 2024-06-04DOI: 10.1038/s41423-024-01182-6
Flavie Naulin, Emma Guilbaud, Lorenzo Galluzzi
{"title":"PARP7 and nucleic acid-driven oncosuppression.","authors":"Flavie Naulin, Emma Guilbaud, Lorenzo Galluzzi","doi":"10.1038/s41423-024-01182-6","DOIUrl":"https://doi.org/10.1038/s41423-024-01182-6","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247638","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 : 2024-05-31DOI: 10.1038/s41423-024-01168-4
Yufang Shi, Andreas Strasser, Douglas R. Green, Eicke Latz, Alberto Mantovani, Gerry Melino
{"title":"Legacy of the discovery of the T-cell receptor: 40 years of shaping basic immunology and translational work to develop novel therapies","authors":"Yufang Shi, Andreas Strasser, Douglas R. Green, Eicke Latz, Alberto Mantovani, Gerry Melino","doi":"10.1038/s41423-024-01168-4","DOIUrl":"10.1038/s41423-024-01168-4","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11214623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183467","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}
The development of distinct dendritic cell (DC) subsets, namely, plasmacytoid DCs (pDCs) and conventional DC subsets (cDC1s and cDC2s), is controlled by specific transcription factors. IRF8 is essential for the fate specification of cDC1s. However, how the expression of Irf8 is regulated is not fully understood. In this study, we identified TRIM33 as a critical regulator of DC differentiation and maintenance. TRIM33 deletion in Trim33fl/fl Cre-ERT2 mice significantly impaired DC differentiation from hematopoietic progenitors at different developmental stages. TRIM33 deficiency downregulated the expression of multiple genes associated with DC differentiation in these progenitors. TRIM33 promoted the transcription of Irf8 to facilitate the differentiation of cDC1s by maintaining adequate CDK9 and Ser2 phosphorylated RNA polymerase II (S2 Pol II) levels at Irf8 gene sites. Moreover, TRIM33 prevented the apoptosis of DCs and progenitors by directly suppressing the PU.1-mediated transcription of Bcl2l11, thereby maintaining DC homeostasis. Taken together, our findings identified TRIM33 as a novel and crucial regulator of DC differentiation and maintenance through the modulation of Irf8 and Bcl2l11 expression. The finding that TRIM33 functions as a critical regulator of both DC differentiation and survival provides potential benefits for devising DC-based immune interventions and therapies.
{"title":"TRIM33 plays a critical role in regulating dendritic cell differentiation and homeostasis by modulating Irf8 and Bcl2l11 transcription","authors":"Xiangyi Shen, Xiaoguang Li, Tao Wu, Tingting Guo, Jiaoyan Lv, Zhimin He, Maocai Luo, Xinyi Zhu, Yujie Tian, Wenlong Lai, Chen Dong, Xiaoyu Hu, Li Wu","doi":"10.1038/s41423-024-01179-1","DOIUrl":"10.1038/s41423-024-01179-1","url":null,"abstract":"The development of distinct dendritic cell (DC) subsets, namely, plasmacytoid DCs (pDCs) and conventional DC subsets (cDC1s and cDC2s), is controlled by specific transcription factors. IRF8 is essential for the fate specification of cDC1s. However, how the expression of Irf8 is regulated is not fully understood. In this study, we identified TRIM33 as a critical regulator of DC differentiation and maintenance. TRIM33 deletion in Trim33fl/fl Cre-ERT2 mice significantly impaired DC differentiation from hematopoietic progenitors at different developmental stages. TRIM33 deficiency downregulated the expression of multiple genes associated with DC differentiation in these progenitors. TRIM33 promoted the transcription of Irf8 to facilitate the differentiation of cDC1s by maintaining adequate CDK9 and Ser2 phosphorylated RNA polymerase II (S2 Pol II) levels at Irf8 gene sites. Moreover, TRIM33 prevented the apoptosis of DCs and progenitors by directly suppressing the PU.1-mediated transcription of Bcl2l11, thereby maintaining DC homeostasis. Taken together, our findings identified TRIM33 as a novel and crucial regulator of DC differentiation and maintenance through the modulation of Irf8 and Bcl2l11 expression. The finding that TRIM33 functions as a critical regulator of both DC differentiation and survival provides potential benefits for devising DC-based immune interventions and therapies.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11214632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183434","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 : 2024-05-28DOI: 10.1038/s41423-024-01175-5
Xiaojing Liu, Fei-Long Meng
{"title":"Correction: Defining two subpopulations of marginal zone B cells","authors":"Xiaojing Liu, Fei-Long Meng","doi":"10.1038/s41423-024-01175-5","DOIUrl":"10.1038/s41423-024-01175-5","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11214612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160891","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 : 2024-05-28DOI: 10.1038/s41423-024-01178-2
Seungwon Ryu, Kyung Ah Kim, Jinwoo Kim, Dong Hun Lee, Yong-Soo Bae, Hajeong Lee, Byoung Choul Kim, Hye Young Kim
Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of the immune response in renal inflammatory diseases such as lupus nephritis. However, the mechanisms underlying ILC2 adhesion and migration in the kidney remain poorly understood. Here, we revealed the critical role of integrin α4β7 in mediating renal ILC2 adhesion and function. We found that integrin α4β7 enables the retention of ILC2s in the kidney by binding to VCAM-1, E-cadherin, or fibronectin on structural cells. Moreover, integrin α4β7 knockdown reduced the production of the reparative cytokine amphiregulin (Areg) by ILC2s. In lupus nephritis, TLR7/9 signaling within the kidney microenvironment downregulates integrin α4β7 expression, leading to decreased Areg production and promoting the egress of ILC2s. Notably, IL-33 treatment upregulated integrin α4β7 and Areg expression in ILC2s, thereby enhancing survival and reducing inflammation in lupus nephritis. Together, these findings highlight the potential of targeting ILC2 adhesion as a therapeutic strategy for autoimmune kidney diseases.
{"title":"The protective roles of integrin α4β7 and Amphiregulin-expressing innate lymphoid cells in lupus nephritis","authors":"Seungwon Ryu, Kyung Ah Kim, Jinwoo Kim, Dong Hun Lee, Yong-Soo Bae, Hajeong Lee, Byoung Choul Kim, Hye Young Kim","doi":"10.1038/s41423-024-01178-2","DOIUrl":"10.1038/s41423-024-01178-2","url":null,"abstract":"Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of the immune response in renal inflammatory diseases such as lupus nephritis. However, the mechanisms underlying ILC2 adhesion and migration in the kidney remain poorly understood. Here, we revealed the critical role of integrin α4β7 in mediating renal ILC2 adhesion and function. We found that integrin α4β7 enables the retention of ILC2s in the kidney by binding to VCAM-1, E-cadherin, or fibronectin on structural cells. Moreover, integrin α4β7 knockdown reduced the production of the reparative cytokine amphiregulin (Areg) by ILC2s. In lupus nephritis, TLR7/9 signaling within the kidney microenvironment downregulates integrin α4β7 expression, leading to decreased Areg production and promoting the egress of ILC2s. Notably, IL-33 treatment upregulated integrin α4β7 and Areg expression in ILC2s, thereby enhancing survival and reducing inflammation in lupus nephritis. Together, these findings highlight the potential of targeting ILC2 adhesion as a therapeutic strategy for autoimmune kidney diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11214630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160848","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 : 2024-05-28DOI: 10.1038/s41423-024-01160-y
Xiaoying Sun, Liu Liu, Jiao Wang, Xiaorong Luo, Meng Wang, Chunxiao Wang, Jiale Chen, Yaqiong Zhou, Hang Yin, Yuanbin Song, Yuanyan Xiong, Hongjin Li, Meiling Zhang, Bo Zhu, Xin Li
Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells (DCs) and T cells, ultimately leading to increased production of cytokines such as interleukin (IL)-23 and IL-17A. It is established that the cGAS-STING pathway is essential for psoriatic inflammation, however, the specific role of cGAS-STING signaling in DCs within this context remains unclear. In this study, we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod (IMQ)-treated mice. Using a conditional Sting-knockout transgenic mouse model, we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17- and IFN-γ-producing T cells in psoriatic inflammation. Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells, and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model. Furthermore, we explored the therapeutic potential of the STING inhibitor C-176, which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response. Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.
{"title":"Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production","authors":"Xiaoying Sun, Liu Liu, Jiao Wang, Xiaorong Luo, Meng Wang, Chunxiao Wang, Jiale Chen, Yaqiong Zhou, Hang Yin, Yuanbin Song, Yuanyan Xiong, Hongjin Li, Meiling Zhang, Bo Zhu, Xin Li","doi":"10.1038/s41423-024-01160-y","DOIUrl":"10.1038/s41423-024-01160-y","url":null,"abstract":"Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells (DCs) and T cells, ultimately leading to increased production of cytokines such as interleukin (IL)-23 and IL-17A. It is established that the cGAS-STING pathway is essential for psoriatic inflammation, however, the specific role of cGAS-STING signaling in DCs within this context remains unclear. In this study, we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod (IMQ)-treated mice. Using a conditional Sting-knockout transgenic mouse model, we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17- and IFN-γ-producing T cells in psoriatic inflammation. Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells, and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model. Furthermore, we explored the therapeutic potential of the STING inhibitor C-176, which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response. Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160893","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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