Pub Date : 2025-06-03DOI: 10.1038/s41423-025-01299-2
Lina Sun, Cangang Zhang, Anjun Jiao, Yanhong Su, Tianzhe Zhang, Qianhao Wang, Yao Ge, Chen Yang, Ning Yuan, Lianjun Zhang, Chenming Sun, Liang Chen, Lilin Ye, Baojun Zhang
Upon antigen recognition, CD8+ T cells undergo robust expansion and differentiation to give rise to effector and memory CD8+ T cells. The spatial determinants of the fate of effector and memory CD8+ T cells during acute infection are poorly understood. By integrating single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics, we revealed that naïve CD8+ T cells adopted a divergent trajectory in which they rapidly differentiated into memory precursor (MP) cells and IFN-responsive cells, with the latter representing the entry point of the effector T-cell lineage. In the spleen, monocytes largely colocalized with CD8+ MP cells following antigen stimulation. Specifically, compared with dendritic cells (DCs), the Ly6ChiCCR2+ subset of monocytes promotes memory CD8+ T-cell differentiation. Mechanistically, monocytes express high levels of membrane-bound transforming growth factor-β (TGF-β), which is activated by thrombospondin-1 (TSP-1) to drive the memory CD8+ T-cell program through Smad signaling. Overall, our study reveals a novel spatial mechanism for CD8+ T-cell fate decisions, shedding light on the importance of monocytes in fostering memory CD8+ T-cell development in a cell‒cell contact- and TGF-β-dependent manner.
{"title":"CCR2+ monocytes promote memory CD8+ T-cell differentiation via membrane-bound TGF-β","authors":"Lina Sun, Cangang Zhang, Anjun Jiao, Yanhong Su, Tianzhe Zhang, Qianhao Wang, Yao Ge, Chen Yang, Ning Yuan, Lianjun Zhang, Chenming Sun, Liang Chen, Lilin Ye, Baojun Zhang","doi":"10.1038/s41423-025-01299-2","DOIUrl":"10.1038/s41423-025-01299-2","url":null,"abstract":"Upon antigen recognition, CD8+ T cells undergo robust expansion and differentiation to give rise to effector and memory CD8+ T cells. The spatial determinants of the fate of effector and memory CD8+ T cells during acute infection are poorly understood. By integrating single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics, we revealed that naïve CD8+ T cells adopted a divergent trajectory in which they rapidly differentiated into memory precursor (MP) cells and IFN-responsive cells, with the latter representing the entry point of the effector T-cell lineage. In the spleen, monocytes largely colocalized with CD8+ MP cells following antigen stimulation. Specifically, compared with dendritic cells (DCs), the Ly6ChiCCR2+ subset of monocytes promotes memory CD8+ T-cell differentiation. Mechanistically, monocytes express high levels of membrane-bound transforming growth factor-β (TGF-β), which is activated by thrombospondin-1 (TSP-1) to drive the memory CD8+ T-cell program through Smad signaling. Overall, our study reveals a novel spatial mechanism for CD8+ T-cell fate decisions, shedding light on the importance of monocytes in fostering memory CD8+ T-cell development in a cell‒cell contact- and TGF-β-dependent manner.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"869-888"},"PeriodicalIF":19.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215090","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 : 2025-06-03DOI: 10.1038/s41423-025-01298-3
Ysbrand Nusse, Paul Kubes
The liver is a sizeable visceral organ whose primary functions involve nutrient metabolism, clearance of toxins, and energy storage. Besides these critical functions, the liver is also a major immunological site. It is populated by several specialized resident immune cells, including B cells, T Cells, dendritic cells, and several populations of macrophages. It is also the site for the production and release of acute-phase proteins during inflammation. One reason for garrisoning these immune sentinels and effectors in the liver is its relative location in the circulatory system. The liver is the first significant organ downstream of the intestine, where blood originating from the intestine enters the liver through the portal vein. This organization facilitates the liver’s uptake and processing of nutrient-rich blood directly from the intestinal source. However, the intestine is also home to trillions of microbes, many of which are commensals but also represent potential pathogens. As such, the portal blood supply represents an avenue for systemic infection. To sterilize the portal blood, the liver immune system filters pathogens, which is primarily accomplished by liver macrophages. Here, we will discuss the major populations of macrophages resident in the liver, their location, functions, development, and role in maintaining the liver in the face of injury and infection.
{"title":"Liver macrophages: development, dynamics, and functions","authors":"Ysbrand Nusse, Paul Kubes","doi":"10.1038/s41423-025-01298-3","DOIUrl":"10.1038/s41423-025-01298-3","url":null,"abstract":"The liver is a sizeable visceral organ whose primary functions involve nutrient metabolism, clearance of toxins, and energy storage. Besides these critical functions, the liver is also a major immunological site. It is populated by several specialized resident immune cells, including B cells, T Cells, dendritic cells, and several populations of macrophages. It is also the site for the production and release of acute-phase proteins during inflammation. One reason for garrisoning these immune sentinels and effectors in the liver is its relative location in the circulatory system. The liver is the first significant organ downstream of the intestine, where blood originating from the intestine enters the liver through the portal vein. This organization facilitates the liver’s uptake and processing of nutrient-rich blood directly from the intestinal source. However, the intestine is also home to trillions of microbes, many of which are commensals but also represent potential pathogens. As such, the portal blood supply represents an avenue for systemic infection. To sterilize the portal blood, the liver immune system filters pathogens, which is primarily accomplished by liver macrophages. Here, we will discuss the major populations of macrophages resident in the liver, their location, functions, development, and role in maintaining the liver in the face of injury and infection.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1178-1189"},"PeriodicalIF":19.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01298-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215091","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 : 2025-06-03DOI: 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
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.
中性粒细胞在il -17介导的气道炎症的进展中起着关键作用，但其病理分化的机制仍然知之甚少。在这项研究中，我们在猪胰腺弹性酶（PPE）诱导的小鼠肺气肿模型中发现了一个独特的肺特异性致病性siglece - f +中性粒细胞群体。与传统的中性粒细胞相比，这些siglece - f +中性粒细胞表现出更高的吞噬活性，增加细胞外陷阱的形成，增加促炎细胞因子的产生，降低IL-10水平。在PPE灌注后急性炎症的早期阶段，肺中IL-17A水平升高，这主要是由γδ+ T细胞驱动的。IL-17A刺激肺上皮/间质细胞分泌粒细胞集落刺激因子（G-CSF），通过JAK2/STAT3通路和pi3k独立的mTOR和p38 MAPK信号通路促进siglece - f +中性粒细胞的分化。中和G-CSF或抑制JAK2/STAT3、mTOR或p38 MAPK信号可显著抑制siglece - f +中性粒细胞的发育，从而减轻肺气肿症状。我们的研究结果强调了Siglec-F+中性粒细胞在pep诱导的肺气肿发病机制中的关键作用，并提示靶向IL-17A/G-CSF轴或G-CSF受体下游信号通路可能是治疗肺气肿的一种有希望的治疗策略。
{"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":"22 7","pages":"791-805"},"PeriodicalIF":19.8,"publicationDate":"2025-06-03","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}
Pub Date : 2025-05-29DOI: 10.1038/s41423-025-01303-9
Junyi Zhao, Xing Guo, Wanli Liu, Conglei Li
{"title":"Cytotoxic T cells meet complement: granzyme K as a new initiator of inflammation","authors":"Junyi Zhao, Xing Guo, Wanli Liu, Conglei Li","doi":"10.1038/s41423-025-01303-9","DOIUrl":"10.1038/s41423-025-01303-9","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 7","pages":"693-695"},"PeriodicalIF":19.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181146","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 : 2025-05-26DOI: 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
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.
{"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":"22 7","pages":"730-742"},"PeriodicalIF":19.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-23DOI: 10.1038/s41423-025-01297-4
Zihen Shen, Xiangpeng Meng, Jai Rautela, Michael Chopin, Nicholas D. Huntington
Natural killer (NK) cells have evolved to detect abnormalities in tissues arising from infection with pathogens, genomic damage, or transformation and respond rapidly to the production of potent proinflammatory and cytolytic mediators. While this acute proinflammatory response is highly efficient at orchestrating sterilizing immunity to pathogens in a matter of days, cellular transformation often avoids the innate detection mechanisms of NK cells. When cellular transformation results in malignancy, tumor cells and/or the tumor microenvironment can evolve additional mechanisms to circumvent NK cell responses, and cancer is now a dominant disease burden worldwide. Here, we review recent advances in our understanding of the combined relationship between malignancies and natural killer (NK) cells, learn from recent clinical efforts in therapeutically targeting natural killer (NK) cells in cancer and outline some emerging therapeutic concepts that aim to improve the innate immune response against cancer.
{"title":"Adjusting the scope of natural killer cells in cancer therapy","authors":"Zihen Shen, Xiangpeng Meng, Jai Rautela, Michael Chopin, Nicholas D. Huntington","doi":"10.1038/s41423-025-01297-4","DOIUrl":"10.1038/s41423-025-01297-4","url":null,"abstract":"Natural killer (NK) cells have evolved to detect abnormalities in tissues arising from infection with pathogens, genomic damage, or transformation and respond rapidly to the production of potent proinflammatory and cytolytic mediators. While this acute proinflammatory response is highly efficient at orchestrating sterilizing immunity to pathogens in a matter of days, cellular transformation often avoids the innate detection mechanisms of NK cells. When cellular transformation results in malignancy, tumor cells and/or the tumor microenvironment can evolve additional mechanisms to circumvent NK cell responses, and cancer is now a dominant disease burden worldwide. Here, we review recent advances in our understanding of the combined relationship between malignancies and natural killer (NK) cells, learn from recent clinical efforts in therapeutically targeting natural killer (NK) cells in cancer and outline some emerging therapeutic concepts that aim to improve the innate immune response against cancer.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 7","pages":"699-711"},"PeriodicalIF":19.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131883","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 : 2025-05-21DOI: 10.1038/s41423-025-01291-w
Haiyuan Shen, Suthat Liangpunsakul, Yasuko Iwakiri, Gyongyi Szabo, Hua Wang
Alcohol-associated liver disease (ALD) is a major global health challenge, with inflammation playing a central role in its progression. As inflammation emerges as a critical therapeutic target, ongoing research aims to unravel its underlying mechanisms. This review explores the immunological pathways of ALD, highlighting the roles of immune cells and their inflammatory mediators in disease onset and progression. We also examine the complex interactions between inflammatory cells and non-parenchymal liver cells, as well as their crosstalk with extra-hepatic organs, including the gut, adipose tissue, and nervous system. Furthermore, we summarize current clinical research on anti-inflammatory therapies and discuss promising therapeutic targets. Given the heterogeneity of ALD-associated inflammation, we emphasize the need for precision medicine to optimize treatment strategies and improve patient outcomes.
{"title":"Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease","authors":"Haiyuan Shen, Suthat Liangpunsakul, Yasuko Iwakiri, Gyongyi Szabo, Hua Wang","doi":"10.1038/s41423-025-01291-w","DOIUrl":"10.1038/s41423-025-01291-w","url":null,"abstract":"Alcohol-associated liver disease (ALD) is a major global health challenge, with inflammation playing a central role in its progression. As inflammation emerges as a critical therapeutic target, ongoing research aims to unravel its underlying mechanisms. This review explores the immunological pathways of ALD, highlighting the roles of immune cells and their inflammatory mediators in disease onset and progression. We also examine the complex interactions between inflammatory cells and non-parenchymal liver cells, as well as their crosstalk with extra-hepatic organs, including the gut, adipose tissue, and nervous system. Furthermore, we summarize current clinical research on anti-inflammatory therapies and discuss promising therapeutic targets. Given the heterogeneity of ALD-associated inflammation, we emphasize the need for precision medicine to optimize treatment strategies and improve patient outcomes.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1190-1204"},"PeriodicalIF":19.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01291-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119053","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}
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.
{"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":"22 7","pages":"776-790"},"PeriodicalIF":19.8,"publicationDate":"2025-05-19","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}
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