JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.191649
John Q Yap, Azadeh Nikouee, Matthew Kim, Quan Cao, David J Rademacher, Jessie E Lau, Ananya Arora, Leila Y Zou, Yuxiao Sun, Luke Szweda, Hesham Sadek, Sharon Elliot, Benjamin Roos, Marilyn K Glassberg, Hong-Long Ji, Xiang Gao, Qunfeng Dong, Qun Sophia Zang
{"title":"Myocardial pyruvate dehydrogenase kinase 4 drives sex-specific cardiac responses to endotoxemia.","authors":"John Q Yap, Azadeh Nikouee, Matthew Kim, Quan Cao, David J Rademacher, Jessie E Lau, Ananya Arora, Leila Y Zou, Yuxiao Sun, Luke Szweda, Hesham Sadek, Sharon Elliot, Benjamin Roos, Marilyn K Glassberg, Hong-Long Ji, Xiang Gao, Qunfeng Dong, Qun Sophia Zang","doi":"10.1172/jci.insight.191649","DOIUrl":"10.1172/jci.insight.191649","url":null,"abstract":"<p><p>Males often experience worse cardiac outcomes than females in sepsis. This study identified pyruvate dehydrogenase kinase 4 (PDK4) as a key mediator of this disparity. PDK4 regulates glucose utilization by inhibiting pyruvate dehydrogenase (PDH) in mitochondria. In a mouse endotoxemia model, a sublethal dose of lipopolysaccharide (LPS, 5 mg/kg) significantly upregulated myocardial PDK4 and induced cardiac dysfunction in males but not females. Cardiac-specific PDK4 overexpression promoted this cardiac dysfunction in both sexes, whereas PDK4 knockout provided protection. In WT males, LPS reduced PDH activity and fatty acid oxidation (FAO) while increasing lactate levels, suggesting a shift toward glycolysis. These effects were exacerbated by PDK4 overexpression but attenuated by knockout. In females, metabolic changes were minimal, aside from reduced FAO in LPS-challenged females overexpressing PDK4. Additionally, a higher LPS dose (8 mg/kg) triggered cardiac dysfunction in females, accompanied by modest upregulation of PDK4, but without changes in PDH or lactate. Dichloroacetate (DCA), restraining PDK-mediated PDH inhibition, improved cardiac function in males but not females during endotoxemia. PDK4 overexpression also exacerbated cardiac mitochondrial damage, reduced mitophagy, and increased oxidative stress and inflammation during endotoxemia - effects that were prevented by PDK4 knockout. These findings suggest that PDK4 drives sex-specific cardiac responses in sepsis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583971","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.182050
Yun-Han Jiang, Meng Zhou, Meng-Di Cheng, Sai Chen, Ying-Qiang Guo
{"title":"Chimeric antigen receptor-engineered cytolytic Tregs reverse pulmonary fibrosis and remodel the fibrotic niche without CRS.","authors":"Yun-Han Jiang, Meng Zhou, Meng-Di Cheng, Sai Chen, Ying-Qiang Guo","doi":"10.1172/jci.insight.182050","DOIUrl":"https://doi.org/10.1172/jci.insight.182050","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a severe diffuse progressive fibrosing interstitial disease leading to respiratory failure and death in the absence of organ transplantation. Substantial evidence has confirmed the pivotal role of fibroblasts in the progression of IPF, yet effective therapeutic options are scarce. Single-cell transcriptomics profiling revealed that among the diverse fibroblast subsets, FAP1+ alveolar fibroblasts (AFs) are pivotal for the progression of IPF. On the basis of these findings, we developed FAP1-targeting chimeric antigen receptor cytotoxic effector regulatory T (CAR-cTregs) cells, which leverage the targeted killing advantage of the currently trending CAR-based immunotherapy for tumors and incorporate the immunosuppressive functions of Tregs to mitigate the inflammation caused by both the disease itself and CAR-T-cell infusion. Accordingly, CAR-cTregs were constructed to effectively eliminate FAP1+ fibroblasts in vitro. This cytotoxic effect can be abrogated by inhibitors of the granzyme-perforin pathway. In the bleomycin-induced PF model, CAR-cTregs were found to reverse fibrosis characterized by diminished recruitment of fibrocytes and improved remodeling of epithelial cells. Together, our results demonstrate that CAR-cTregs can serve as a promising therapeutic option for IPF and provide a novel strategy for treating multiple chronic inflammatory diseases by inducing both cytotoxicity and immunosuppression.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583954","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.188843
Nicole L Huang, Jessica G Ortega, Kyleigh Kimbrell, Joah Lee, Lauren N Scott, Esther M Peluso, Sarah J Wang, Ellie Y Kao, Kristy Kim, Jarod Olay, Jaden N Nguyen, Zoe Quandt, Trevor E Angell, Maureen A Su, Melissa G Lechner
{"title":"Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy.","authors":"Nicole L Huang, Jessica G Ortega, Kyleigh Kimbrell, Joah Lee, Lauren N Scott, Esther M Peluso, Sarah J Wang, Ellie Y Kao, Kristy Kim, Jarod Olay, Jaden N Nguyen, Zoe Quandt, Trevor E Angell, Maureen A Su, Melissa G Lechner","doi":"10.1172/jci.insight.188843","DOIUrl":"10.1172/jci.insight.188843","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption, and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic β-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. We identify expansion of CD4+ T follicular helper (Tfh) cells expressing IL-21 and IFN-γ as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN-γ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN-γ both signal through JAK/STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583972","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.193496
Elnaz Ghotbi, Edem Tchegnon, Ze Yu, Tracey Shipman, Zhiguo Chen, Yumeng Zhang, Renee M McKay, Chao Xing, Chung-Ping Liao, Lu Q Le
{"title":"Hair follicle epithelial stem cells contribute to interfollicular epidermis during homeostasis.","authors":"Elnaz Ghotbi, Edem Tchegnon, Ze Yu, Tracey Shipman, Zhiguo Chen, Yumeng Zhang, Renee M McKay, Chao Xing, Chung-Ping Liao, Lu Q Le","doi":"10.1172/jci.insight.193496","DOIUrl":"https://doi.org/10.1172/jci.insight.193496","url":null,"abstract":"<p><p>Mammalian skin is a vital barrier with the epidermis serving as its protective outer layer, continually undergoing renewal. Given that loss of the epidermis or its barrier function is lethal for mammals, multiple stem cell populations likely exist for the interfollicular epidermis (IFE), enhancing evolutionary survival. Here, we demonstrate that transcription factor KROX20 marks a heterogeneous stem cell population in the upper and middle mouse hair follicle (HF), partially overlapping with known HF stem cell markers in those regions. Lineage tracing in mice using different reporter lines shows that Krox20-lineage cells migrate from the HF to the IFE, contributing to both basal and suprabasal layers during adulthood. Spatial transcriptomics data corroborate our findings. Depletion of epithelial Krox20-expressing cells leads to epidermal hyperplasia and a disruption of stratification during morphogenesis and homeostasis. Our study highlights the contribution of hair follicle Krox20-lineage cells to the IFE and the regulation of epidermal homeostasis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583956","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.191017
Dominika Sosnowska, Tik Shing Cheung, Jit Sarkar, James W Opzoomer, Karen T Feehan, Joanne E Anstee, Chloé Amelia Woodman, Mohamed Reda Keddar, Kalum Clayton, Samira Ali, William Macmorland, Dorothy D Yang, James Rosekilly, Cheryl E Gillett, Francesca D Ciccarelli, Richard Buus, James Spicer, Anita Grigoriadis, James N Arnold
{"title":"Tumor microenvironments with an active type-I interferon response are sensitive to inhibitors of heme degradation.","authors":"Dominika Sosnowska, Tik Shing Cheung, Jit Sarkar, James W Opzoomer, Karen T Feehan, Joanne E Anstee, Chloé Amelia Woodman, Mohamed Reda Keddar, Kalum Clayton, Samira Ali, William Macmorland, Dorothy D Yang, James Rosekilly, Cheryl E Gillett, Francesca D Ciccarelli, Richard Buus, James Spicer, Anita Grigoriadis, James N Arnold","doi":"10.1172/jci.insight.191017","DOIUrl":"https://doi.org/10.1172/jci.insight.191017","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is highly heterogeneous and can dictate the success of therapeutic interventions. Identifying TMEs that are susceptible to specific therapeutic interventions paves the way for more personalized and effective treatments. In this study, using a spontaneous murine model of breast cancer, we characterize a TME that is responsive to inhibitors of the heme degradation pathway mediated by heme oxygenase (HO), resulting in CD8+ T- and NK-cell-dependent tumor control. A hallmark of this TME is a chronic type-I interferon (IFN) signal that is directly involved in orchestrating the anti-tumor immune response. Importantly, we identify that similar TMEs exist in human breast cancer which are associated with patient prognosis. Leveraging these observations, we demonstrate that combining a STING agonist, which induces type-I IFN responses, with an HO inhibitor produces a synergistic effect leading to superior tumor control. This study highlights HO activity as a potential resistance mechanism for type-I IFN responses in cancer offering a novel avenue for overcoming immune evasion in cancer therapy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583959","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.187684
Yang Liu, Lizhi Pang, Fatima Khan, Junyan Wu, Fei Zhou, Craig Horbinski, Shideng Bao, Jennifer S Yu, Justin D Lathia, Peiwen Chen
{"title":"Glycoprotein NMB mediates bidirectional GSC-TAM interactions to promote tumor progression.","authors":"Yang Liu, Lizhi Pang, Fatima Khan, Junyan Wu, Fei Zhou, Craig Horbinski, Shideng Bao, Jennifer S Yu, Justin D Lathia, Peiwen Chen","doi":"10.1172/jci.insight.187684","DOIUrl":"https://doi.org/10.1172/jci.insight.187684","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of GBM stem cells (GSCs) that interaction with surrounding cells, including infiltrating tumor-associated macrophages and microglia (TAMs). While GSCs and TAMs are in close proximity and likely interact to coordinate tumor growth, a limited number of mechanisms have been identified that support their communication. Here, we identified glycoprotein NMB (GPNMB) as a key factor mediating a unique bidirectional interaction between GSCs and TAMs in GBM. Specifically, GSCs educated macrophages and microglia to preferentially express GPNMB in the GBM tumor microenvironment. As a result, TAM-secreted GPNMB interacted with its receptor CD44 on GSCs to promote their glycolytic and self-renewal abilities via activating the PYK2/RSK2 signaling axis. Disrupting GPNMB-mediated GSC-TAM interplay suppressed tumor progression and self-renewal in GBM mouse models. Our study found a protumor function of GPNMB-mediated GSC-TAM bidirectional communication and supports GPNMB as a promising therapeutic target for GBM.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583967","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.183123
Jennifer A Sequoia, Naomi L Haddock, Paw Mar Gay, Layla J Barkal, Purnima Narasimhan, Nadine Martinez, Virginia D Winn, Paul L Bollyky
{"title":"Identification of bacteriophage DNA in human umbilical cord blood.","authors":"Jennifer A Sequoia, Naomi L Haddock, Paw Mar Gay, Layla J Barkal, Purnima Narasimhan, Nadine Martinez, Virginia D Winn, Paul L Bollyky","doi":"10.1172/jci.insight.183123","DOIUrl":"https://doi.org/10.1172/jci.insight.183123","url":null,"abstract":"<p><p>Bacteriophages, viruses that parasitize bacteria, are abundant in the human microbiome and may influence human health, in part, through their interactions with bacterial hosts. Whether endogenous bacteriophages or their products are vertically transmitted from mother to fetus during human pregnancy is not known. Here, we searched for bacteriophage sequences from five bacteriophage databases (474,031 total sequences) in cell-free DNA (cfDNA) of paired maternal and umbilical cord blood samples from two independent cohorts. First, we sequenced cfDNA from 10 pairs of maternal and cord blood samples, including four pairs affected by preeclampsia. We validated our findings in a previously published dataset of 62 paired maternal and cord blood samples, including 43 pairs from preterm or chorioamnionitis-affected deliveries. We identified 94 and 596 bacteriophage sequences in maternal and cord blood cfDNA samples from the first and second cohort, respectively. We identified 58 phage sequences across maternal-infant dyads and 581 phage sequences that were unique to a single sample. We did not identify any phage sequences consistently associated with preeclampsia, preterm, or chorioamnionitis-affected samples. This study demonstrated the presence of bacteriophage DNA in human cord blood at birth, providing evidence that the human fetus is exposed to bacteriophage DNA in utero.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583969","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.181946
Philip K Farahat, Chino Kumagai-Cresse, Raquel L Aragón, Feiyang Ma, Justin K Amakor, Alejandro Espinoza, Irina Kramerova, Robert J Jimenez, Bradley M Smith, Jesus Perez, Rachelle H Crosbie, Apoorva H Nagendra, Jackie McCourt-Towner, Gerald Coulis, Oluwatayo F Ikotun, April D Pyle, Matteo Pellegrini, Elizabeth M McNally, S Armando Villalta, Melissa J Spencer
{"title":"Macrophage-derived Spp1 promotes intramuscular fat in dystrophic muscle.","authors":"Philip K Farahat, Chino Kumagai-Cresse, Raquel L Aragón, Feiyang Ma, Justin K Amakor, Alejandro Espinoza, Irina Kramerova, Robert J Jimenez, Bradley M Smith, Jesus Perez, Rachelle H Crosbie, Apoorva H Nagendra, Jackie McCourt-Towner, Gerald Coulis, Oluwatayo F Ikotun, April D Pyle, Matteo Pellegrini, Elizabeth M McNally, S Armando Villalta, Melissa J Spencer","doi":"10.1172/jci.insight.181946","DOIUrl":"https://doi.org/10.1172/jci.insight.181946","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder involving cycles of muscle degeneration and regeneration, leading to accumulation of intramuscular fibrosis and fat. Ablation of Osteopontin/Spp1 in a murine model of DMD (mdx) improves the dystrophic phenotype, but the source of Spp1 and its impact on target cells in dystrophic muscles remain unknown. In dystrophic muscles, macrophages are the predominate infiltrating leukocyte and express high levels of Spp1. We used macrophage-specific ablation combined with single-cell transcriptional profiling to uncover the impact of macrophage-derived Spp1 on cell-cell interactions in mdx muscles. Ablation of macrophage-specific Spp1 (cKO) correlated with reduction of 2 PDGFRa+ stromal cell populations, expressing Lifr+ and Procr+. Sorting and transcriptional profiling of these populations confirmed that they are enriched in adipogenesis genes and are highly related to fibroadipogenic precursors (FAPS). These adipogenic stromal cells (ASC) displayed more adipogenic potential in vitro compared with FAPS, likely due to a more differentiated state. Reduction of ASCs correlated with reduced intramuscular diaphragmatic fat and improved diaphragm function. These data suggest a role for myeloid-derived Spp1 in the differentiation of stromal cells towards an adipogenic fate, leading to accumulation of intramuscular fat in dystrophic muscles.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583970","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.190244
Valentina Tassinari, Marta Kaciulis, Stefano Petrai, Helena Stabile, Angelina Pernazza, Martina Leopizzi, Valeria Di Maio, Francesca Belleudi, Danilo Ranieri, Vanessa Mancini, Innocenza Palaia, Federica Tanzi, Ludovica Lospinoso Severini, Silvia Ruggeri, Maria Emanuela Greco, Giovanni Bernardini, Alessandra Zingoni, Marco Cippitelli, Cristina Cerboni, Alessandra Soriani
{"title":"ADAR1 expression is associated with cervical cancer progression and negatively regulates NK cell activity.","authors":"Valentina Tassinari, Marta Kaciulis, Stefano Petrai, Helena Stabile, Angelina Pernazza, Martina Leopizzi, Valeria Di Maio, Francesca Belleudi, Danilo Ranieri, Vanessa Mancini, Innocenza Palaia, Federica Tanzi, Ludovica Lospinoso Severini, Silvia Ruggeri, Maria Emanuela Greco, Giovanni Bernardini, Alessandra Zingoni, Marco Cippitelli, Cristina Cerboni, Alessandra Soriani","doi":"10.1172/jci.insight.190244","DOIUrl":"https://doi.org/10.1172/jci.insight.190244","url":null,"abstract":"<p><p>ADAR1 edits double-stranded RNAs (dsRNAs) by deaminating adenosines into inosines, preventing aberrant activation of innate immunity by endogenous dsRNAs, which may resemble viral structures. Several tumors exploit ADAR1 to evade immune surveillance; indeed, its deletion reduces tumor viability and reshapes infiltrating leukocytes. Here we investigated the role of ADAR1 in immune evasion mechanisms during cervical cancer (CC) progression. Patients' biopsy samples showed higher ADAR1 expression already in premalignant lesions (squamous intraepithelial lesions [SIL]) and a substantially reduced percentage of infiltrating CD7+ innate cells in in situ and invasive carcinomas compared with normal mucosa, with CD56+ NK cells showing phenotypic alterations that may have affected their functional responses. In CC-derived cell lines (SiHa, CaSki), ADAR1 silencing reduced cell proliferation, an effect further enhanced by exogenous IFN-β administration. It also induced proinflammatory gene expression, as demonstrated by RNA-Seq analysis, and conditioned supernatants collected from these cells activated several NK cell effector functions. NK cell infiltration and activation were also confirmed in organotypic 3D tissue models of SiHa cells knocked out for ADAR1. In conclusion, ADAR1 expression increased with CC progression and was accompanied by alterations in tumor-infiltrating NK cells, but its silencing in CC-derived cell lines potentiated antitumor NK cell activities. Thus, ADAR1 inhibition may represent a therapeutic perspective for CC and possibly other malignancies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583960","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}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.187018
Estelle Kim, Brian K Wells, Hannah Indralingam, Yujuan Su, Jamie Verheyden, Xin Sun
{"title":"Allergen induces pulmonary neuroendocrine cell hyperplasia in a model of asthma.","authors":"Estelle Kim, Brian K Wells, Hannah Indralingam, Yujuan Su, Jamie Verheyden, Xin Sun","doi":"10.1172/jci.insight.187018","DOIUrl":"https://doi.org/10.1172/jci.insight.187018","url":null,"abstract":"<p><p>Asthma is characterized by exacerbated response to triggers such as allergen. While pulmonary neuroendocrine cells (PNECs), a rare population of airway epithelial cells, are essential for amplifying allergen-induced asthma response, how PNECs are regulated to achieve this role remains poorly understood. Here we show that in the adult mouse airway, inactivation of achaete-scute-like protein 1 gene in PNECs led to loss of these cells. Intriguingly, exposure of these mutants to house dust mites (HDM), a common allergen, led to reappearance of PNECs. Similarly, exposure of wild-type mice to HDM led to PNEC hyperplasia, a result of proliferation of existing PNECs and transdifferentiation from club cells. Single-cell RNA-Seq experiments revealed PNEC heterogeneity, including the emergence of an allergen-induced PNEC subtype. Notch signaling was downregulated in HDM-treated airway, and treatment with Notch agonist prevented PNEC hyperplasia. These findings together suggest that HDM-induced PNEC hyperplasia may contribute to exacerbated asthma response.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583961","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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