Cellular &Molecular Immunology最新文献_第2页

Human liver immunology: from in vitro models to new insights. 人肝脏免疫学：从体外模型到新见解。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-02 DOI: 10.1038/s41423-025-01312-8

Milad Rezvani

{"title":"Human liver immunology: from in vitro models to new insights.","authors":"Milad Rezvani","doi":"10.1038/s41423-025-01312-8","DOIUrl":"https://doi.org/10.1038/s41423-025-01312-8","url":null,"abstract":"The liver hosts a variety of immune cells while creating a tolerogenic environment under homeostatic conditions. However, most chronic liver diseases shift toward inflammation over time. Understanding and intercepting the crosstalk between various immune cells and liver tissue is crucial, as it is often the rate-limiting factor in preclinical drug development. Owing to significant interspecies differences in liver immunology, human models, such as classical cocultures or organogenesis-inspired liver organoids with immune compartments, are becoming essential for advancing the field. Therefore, this review evaluates human-specific models of hepatic-immune crosstalk and assesses a range of models from basic 2D cultures to microphysiological systems (MPSs) and advanced multitissue organoids. It serves as a guide for experimentalists to identify suitable approaches. For example, traditional cocultures offer robustness, reductionist approaches, and modularity but have limited spatial fidelity and cell heterogeneity. In contrast, multitissue organoids inspired by mammalian ontogeny are created from pluripotent stem cells and integrate multiple tissue niche-constituting cells, which include Kupffer-like cells. In conclusion, this review discusses progress in human liver immunology modeling and highlights limitations and numerous untapped opportunities. These include the potential to model in vitro autoimmunity and more complex myeloid inflammatory responses, incorporating contributions from embryonic tissue and bone marrow. Additionally, future in vitro models may include hard-to-culture populations such as neutrophils.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552479","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}

引用次数: 0

Synergistic effects of LCN2 and TWEAK on the progression of psoriasis. LCN2和TWEAK对银屑病进展的协同作用。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-05-15 DOI: 10.1038/s41423-025-01292-9

Kaixuan Ren, Xueting Peng, Xudong Duan, Rongfang Feng, Christopher Cook, Mei Lu, Min Li, Hanjiang Gu, Xiaoyu Wang, Guorong Deng, Huiqun Ma, Yale Liu, Yumin Xia

{"title":"Synergistic effects of LCN2 and TWEAK on the progression of psoriasis.","authors":"Kaixuan Ren, Xueting Peng, Xudong Duan, Rongfang Feng, Christopher Cook, Mei Lu, Min Li, Hanjiang Gu, Xiaoyu Wang, Guorong Deng, Huiqun Ma, Yale Liu, Yumin Xia","doi":"10.1038/s41423-025-01292-9","DOIUrl":"10.1038/s41423-025-01292-9","url":null,"abstract":"Lipocalin 2 (LCN2) and the TWEAK/Fn14 signaling pathways are pivotal in psoriasis, influencing epidermal development, inflammatory cell chemotaxis, and inflammatory factor release. Despite their significant roles, the intricate relationship between LCN2 and TWEAK/Fn14 pathways remains unclear. Our study revealed the correlation between the expression of TWEAK, LCN2, and Fn14 in psoriatic lesions. We found that TWEAK is expressed by keratinocytes and macrophages, while LCN2 is expressed by keratinocytes and neutrophils. Surface plasmon resonance experiments demonstrated binding between LCN2 and Fn14, which was further validated by co-immunoprecipitation and cellular co-localization via immunofluorescence. In vitro, LCN2 promoted macrophage differentiation and TWEAK secretion, enhanced TWEAK and Fn14 expression in keratinocytes, and activated the MAPK signaling pathway. TWEAK upregulated LCN2 expression in neutrophils but not in keratinocytes. Bulk RNA-seq analysis revealed a synergistic effect of LCN2 and TWEAK in promoting inflammatory cytokine expression in keratinocytes, with enhanced MAPK pathway activation in the presence of M5 cytokines. Lcn2 knockout reduced Fn14 expression in skin lesions and serum TWEAK levels of imiquimod-induced murine psoriasis model, while Fn14 knockout attenuated the epidermal hyperplasia-promoting effects of TWEAK and LCN2. Overexpression of Fn14 in keratinocytes led to higher TWEAK expression upon LCN2 stimulation, suggesting a self-reinforcing loop among TWEAK, LCN2, and Fn14. We propose that LCN2 synergizes with TWEAK through Fn14 to drive psoriasis pathogenesis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":"760-775"},"PeriodicalIF":21.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076321","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}

引用次数: 0

Cytotoxic T cells meet complement: granzyme K as a new initiator of inflammation. 细胞毒性T细胞遇到补体：颗粒酶K作为炎症的新启动器。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-05-29 DOI: 10.1038/s41423-025-01303-9

Junyi Zhao, Xing Guo, Wanli Liu, Conglei Li

引用次数: 0

Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy. 靶向Lp-PLA2通过恢复心磷脂介导的线粒体自噬抑制矽肺中纤维化单核细胞来源的巨噬细胞。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-05-19 DOI: 10.1038/s41423-025-01288-5

Shifeng Li, Hong Xu, Shupeng Liu, Jinkun Hou, Yueyin Han, Chen Li, Yupeng Li, Gaigai Zheng, Zhongqiu Wei, Fang Yang, Shuwei Gao, Shiyao Wang, Jing Geng, Huaping Dai, Chen Wang

{"title":"Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy.","authors":"Shifeng Li, Hong Xu, Shupeng Liu, Jinkun Hou, Yueyin Han, Chen Li, Yupeng Li, Gaigai Zheng, Zhongqiu Wei, Fang Yang, Shuwei Gao, Shiyao Wang, Jing Geng, Huaping Dai, Chen Wang","doi":"10.1038/s41423-025-01288-5","DOIUrl":"10.1038/s41423-025-01288-5","url":null,"abstract":"Monocyte-derived macrophages (MoMacs) are the most important effector cells that cause pulmonary fibrosis. However, the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear. Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs, identified as Spp1hiMacs, which remain in an immature transitional state of differentiation during silicosis. This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by Pla2g7)-acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1)-cardiolipin (CL) signaling pathway, which interferes with Spp1hiMac differentiation. We demonstrated that in SiO2-induced MoMacs, Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1, resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects. Simultaneously, lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm, which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways. Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":"776-790"},"PeriodicalIF":21.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101429","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}

引用次数: 0

Adjusting the scope of natural killer cells in cancer therapy. 调整自然杀伤细胞在癌症治疗中的作用范围。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-05-23 DOI: 10.1038/s41423-025-01297-4

Zihen Shen, Xiangpeng Meng, Jai Rautela, Michael Chopin, Nicholas D Huntington

引用次数: 0

Cholinergic B cells: New players in immune regulation and tissue homeostasis. 胆碱能B细胞：免疫调节和组织稳态的新参与者。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-05-30 DOI: 10.1038/s41423-025-01300-y

Fan Xiao, Lam Ng, Kongyang Ma, Chong Deng, Xiaoxia Zhu, Hejian Zou, Haijing Wu, Liwei Lu

引用次数: 0

CD39 as a metabolic rheostat of immunoregulation. CD39作为免疫调节的代谢变阻器。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-06-24 DOI: 10.1038/s41423-025-01302-w

Vincenzo Barnaba, Silvano Sozzani

引用次数: 0

γδ⁺ T-cell-derived IL-17A stimulates airway epithelial/stromal cells to secrete G-CSF, promoting lung-specific pathogenic Siglec-F⁺ neutrophil development in PPE-induced emphysema. γδ+ t细胞源性IL-17A刺激气道上皮/间质细胞分泌G-CSF，促进肺特异性致病性siglece - f +中性粒细胞在肺气肿中的发育。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-06-03 DOI: 10.1038/s41423-025-01301-x

JungHyub Hong, Myeong-Ho Kang, Jinjoo Lee, Min-Suk Cha, Yoe-Sik Bae, Hye Young Kim, Yong Taik Lim, Yong-Soo Bae

{"title":"γδ+ T-cell-derived IL-17A stimulates airway epithelial/stromal cells to secrete G-CSF, promoting lung-specific pathogenic Siglec-F+ neutrophil development in PPE-induced emphysema.","authors":"JungHyub Hong, Myeong-Ho Kang, Jinjoo Lee, Min-Suk Cha, Yoe-Sik Bae, Hye Young Kim, Yong Taik Lim, Yong-Soo Bae","doi":"10.1038/s41423-025-01301-x","DOIUrl":"10.1038/s41423-025-01301-x","url":null,"abstract":"Neutrophils play a pivotal role in the progression of IL-17-mediated airway inflammation, but the mechanisms underlying their pathological differentiation remain poorly understood. In this study, we identified a distinct population of lung-specific pathogenic Siglec-F+ neutrophils in a porcine pancreatic elastase (PPE)-induced mouse model of emphysema. Compared with conventional neutrophils, these Siglec-F+ neutrophils exhibited increased phagocytic activity, increased extracellular trap formation, increased production of proinflammatory cytokines, and reduced IL-10 levels. During the early phase of acute inflammation following PPE instillation, IL-17A levels in the lungs increase, which is driven primarily by γδ+ T cells. IL-17A stimulated lung epithelial/stromal cells to secrete granulocyte colony-stimulating factor (G-CSF), which promoted the differentiation of Siglec-F+ neutrophils via the JAK2/STAT3 pathway and the PI3K-independent mTOR and p38 MAPK signaling pathways. Neutralizing G-CSF or inhibiting JAK2/STAT3, mTOR or p38 MAPK signaling significantly suppressed Siglec-F+ neutrophil development, resulting in the alleviation of emphysematous symptoms. Our findings underscore the crucial role of Siglec-F+ neutrophils in the pathogenesis of PPE-induced emphysema and suggest that targeting the IL-17A/G-CSF axis or G-CSF receptor downstream signaling pathways may represent a promising therapeutic strategy for treating emphysema.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":"791-805"},"PeriodicalIF":21.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215092","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}

引用次数: 0

Sexual dimorphism of lung immune-regulatory units imprint biased pulmonary fibrosis. 肺免疫调节单位的性别二态性印记偏倚性肺纤维化。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-05-14 DOI: 10.1038/s41423-025-01293-8

Peng Xiang, Liwen Wang, Xu Feng, Qi Guo, Genqing Xie, Langqing Sheng, Linyun Chen, Jianhui Teng, Jinlin Yang, Xuecheng Wu, Xi Peng, Renbin Lu, Xianghang Luo, Jie Wen, Hai-Yan Zhou

{"title":"Sexual dimorphism of lung immune-regulatory units imprint biased pulmonary fibrosis.","authors":"Peng Xiang, Liwen Wang, Xu Feng, Qi Guo, Genqing Xie, Langqing Sheng, Linyun Chen, Jianhui Teng, Jinlin Yang, Xuecheng Wu, Xi Peng, Renbin Lu, Xianghang Luo, Jie Wen, Hai-Yan Zhou","doi":"10.1038/s41423-025-01293-8","DOIUrl":"10.1038/s41423-025-01293-8","url":null,"abstract":"Pulmonary fibrosis (PF) is sexually dimorphic, with a relatively high prevalence and severity in males; however, the mechanism remains unclear. Our study revealed pronounced sexual dimorphism of immune cell genes in the lung, among which grancalcin (GCA) showed profound sex differences. GCA was produced by lung-infiltrating bone marrow macrophages triggered by heightened inflammation in the lung. However, a unique HTR2C+ alveolar macrophage population enriched in female lungs metabolically reprogramed bone marrow-derived macrophages and constrained local GCA amplification. As a novel chemokine, GCA bound to protein tyrosine phosphatase receptor type T (PTPRT) in Th17 cells and facilitated pathogenic lung infiltration by activating the ROCK1-MLC pathway, thus aggravating lung fibrosis. Notably, both GCA and Th17 cells abundantly accumulated in lung biopsies from male PF patients but not in those from female patients. GCA-neutralizing antibodies in combination with pirfenidone, a prescribed medication for treating fibrosis, provided superior effectiveness and survival rates against PF compared with treatment with pirfenidone alone. Overall, our findings reveal that sex-biased lung fibrosis is shaped by lung immune-regulatory units, which could be targeted to limit lung fibrosis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":"743-759"},"PeriodicalIF":21.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983072","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}

引用次数: 0

Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease. 人CD39的反义蛋白在炎症性肠病中调节免疫代谢失调。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-07-01 Epub Date: 2025-05-26 DOI: 10.1038/s41423-025-01295-6

Lina Zhang, Cortney Cagle, Du Hanh Nguyen, Graziela Scheuer Gomes, Barbora Gromova, Eva Csizmadia, Arian Karimitar, Ghee Rye Lee, Guanqing Chen, Efi Kokkotou, Laurie Grossberg, Sizun Jiang, Adam S Cheifetz, Satya K Kota, Maria Serena Longhi

{"title":"Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease.","authors":"Lina Zhang, Cortney Cagle, Du Hanh Nguyen, Graziela Scheuer Gomes, Barbora Gromova, Eva Csizmadia, Arian Karimitar, Ghee Rye Lee, Guanqing Chen, Efi Kokkotou, Laurie Grossberg, Sizun Jiang, Adam S Cheifetz, Satya K Kota, Maria Serena Longhi","doi":"10.1038/s41423-025-01295-6","DOIUrl":"10.1038/s41423-025-01295-6","url":null,"abstract":"Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease (IBD). CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine, an immune metabolite that is key to tissue homeostasis. Human CD39 is regulated by an endogenous antisense RNA (CD39-AS) that is markedly elevated in IBD Tregs and Th17 cells. In this study, we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients. We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells. Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD. In Th17 cells, silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health. These metabolic effects are also noted in a model of experimental colitis in humanized mice, along with reduced disease activity. Thus, in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity, decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes. Mechanistically, activation of HIF-1α and STAT3 results in the upregulation of CD39-AS in IBD cells. In conclusion, CD39-AS is an important modulator of Treg and Th17 cell metabolism. Interference with this antisense RNA, or the factors favoring its upregulation, might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":"730-742"},"PeriodicalIF":21.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141552","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}

引用次数: 0