Pub Date : 2025-11-24DOI: 10.1016/j.ajpath.2025.11.001
Qiufen Xun, Qing Yang, Guofeng Zhu, Wei Wang
Pulmonary arterial hypertension is a disease characterized by abnormally high pulmonary arterial blood pressures caused by a variety of heterogeneous diseases and different pathogenetic mechanisms. This study establishes a hypoxic pulmonary hypertension (HPH) mouse model, revealing cullin 2 (CUL2)'s critical role in disease pathogenesis. Hypoxia up-regulates CUL2 in HPH lungs, whereas CUL2 knockdown alleviates the Warburg effect, right ventricular dysfunction, and pulmonary fibrosis. In vitro, CUL2 depletion suppresses proliferation, adhesion, and tube formation in hypoxic pulmonary arterial endothelial cells. Mechanistically, CUL2 enhances glycolysis by up-regulating lactate dehydrogenase A (LDHA)/phosphofructokinase, liver type (PFKL), and their overexpression rescues CUL2-silencing effects. Furthermore, hypoxia-induced proline hydroxylase 2 (PHD2) down-regulation stabilizes hypoxia-inducible factor-1α (HIF-1α), which directly binds the CUL2 promoter to enhance its expression. These findings unveil a novel PHD2/HIF-1α/CUL2 axis that promotes vascular remodeling via glycolysis, offering a potential therapeutic target for pulmonary arterial hypertension. In conclusion, this work demonstrated that under hypoxia condition, PHD2-mediated hydroxylation of HIF-1α was blocked and the expression of HIF-1α was elevated in HPH mice. High levels of HIF-1α elevated the transcription and expression of CUL2 and increased the Warburg effect, thereby accelerating HPH development.
{"title":"Cullin 2 Elevates the Warburg Effect to Accelerate the Development of Hypoxic Pulmonary Hypertension","authors":"Qiufen Xun, Qing Yang, Guofeng Zhu, Wei Wang","doi":"10.1016/j.ajpath.2025.11.001","DOIUrl":"10.1016/j.ajpath.2025.11.001","url":null,"abstract":"<div><div>Pulmonary arterial hypertension is a disease characterized by abnormally high pulmonary arterial blood pressures caused by a variety of heterogeneous diseases and different pathogenetic mechanisms. This study establishes a hypoxic pulmonary hypertension (HPH) mouse model, revealing cullin 2 (CUL2)'s critical role in disease pathogenesis. Hypoxia up-regulates CUL2 in HPH lungs, whereas CUL2 knockdown alleviates the Warburg effect, right ventricular dysfunction, and pulmonary fibrosis. <em>In vitro</em>, CUL2 depletion suppresses proliferation, adhesion, and tube formation in hypoxic pulmonary arterial endothelial cells. Mechanistically, CUL2 enhances glycolysis by up-regulating lactate dehydrogenase A (LDHA)/phosphofructokinase, liver type (PFKL), and their overexpression rescues CUL2-silencing effects. Furthermore, hypoxia-induced proline hydroxylase 2 (PHD2) down-regulation stabilizes hypoxia-inducible factor-1α (HIF-1α), which directly binds the <em>CUL2</em> promoter to enhance its expression. These findings unveil a novel PHD2/HIF-1α/CUL2 axis that promotes vascular remodeling via glycolysis, offering a potential therapeutic target for pulmonary arterial hypertension. In conclusion, this work demonstrated that under hypoxia condition, PHD2-mediated hydroxylation of HIF-1α was blocked and the expression of HIF-1α was elevated in HPH mice. High levels of HIF-1α elevated the transcription and expression of CUL2 and increased the Warburg effect, thereby accelerating HPH development.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 369-387"},"PeriodicalIF":3.6,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ajpath.2025.09.004
Steven L. Carroll
{"title":"A Seminal Work That Defined the Pathology of Frontotemporal Dementias and the Concept of TDP-43 Proteinopathies","authors":"Steven L. Carroll","doi":"10.1016/j.ajpath.2025.09.004","DOIUrl":"10.1016/j.ajpath.2025.09.004","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 12","pages":"Pages 2251-2253"},"PeriodicalIF":3.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ajpath.2025.08.012
Jing Li , Meixue Chen , Lingling Lu , Yinmiao Wang , Wei Wu , Yanhong Feng
Pediatric asthma is a respiratory disease in which M2 macrophages play a critical role. Here, the role and molecular mechanism of lysophosphatidic acid receptor 5 (LPAR5) were investigated in pediatric asthma through in vivo and in vitro experiments. LPAR5 expression was increased in peripheral blood mononuclear cells from children with asthma. In an ovalbumin-induced neonatal asthmatic mouse model, LPAR5 antagonist alleviated airway inflammation by suppressing the release of inflammatory cytokines and inflammatory cell infiltration. Ovalbumin-induced M2 macrophage activation in neonatal mouse lung tissue was suppressed by LPAR5 antagonist, accompanied by decreased YM1 protein (encoded by chitinase 3 like 1) secretion. Differentiated THP-1 cells were stimulated with IL-4 to mimic M2 macrophages in vitro. M2 macrophage activation was reduced by both LPAR5 antagonist or LPAR5 knockdown. Furthermore, KLF transcription factor 5 (KLF5) was significantly up-regulated and positively correlated with LPAR5 expression in peripheral blood mononuclear cells from children with asthma. KLF5 bound to the promoter of LPAR5 and transcriptionally promoted LPAR5 expression. LPAR5 overexpression increased M2 macrophage activation in KLF5-depleted THP-1 cells. The underlying mechanism of LPAR5 was investigated by phosphorylomics analysis, which identified mitogen-activated protein kinase kinase kinase 7 as a possible downstream effector. The results showed that LPAR5 antagonist attenuated airway inflammation in neonatal mice by decreasing M2 macrophage activation. KLF5 positively regulates the expression of LPAR5, which further increased the phosphorylation of mitogen-activated protein kinase kinase kinase 7 protein in macrophages. This article highlights that LPAR5 might serve as a potential target in pediatric asthma.
小儿哮喘是一种呼吸系统疾病，M2巨噬细胞在其中起关键作用。本研究通过体内和体外实验，探讨溶血磷脂酸受体5 （LPAR5）在小儿哮喘中的作用及分子机制。哮喘患儿外周血单个核细胞中LPAR5表达升高。在卵清蛋白诱导的新生儿哮喘小鼠模型中，LPAR5拮抗剂通过抑制炎症细胞因子的释放和炎症细胞的浸润来减轻气道炎症。LPAR5拮抗剂可抑制卵清蛋白诱导的新生小鼠肺组织中M2巨噬细胞的活化，并伴有YM1蛋白（由几丁质酶3 like 1编码）分泌减少。用IL-4刺激分化的THP-1细胞模拟M2巨噬细胞。LPAR5拮抗剂或LPAR5敲低均可降低M2巨噬细胞的活化。此外，哮喘患儿外周血单个核细胞中KLF转录因子5 （KLF5）显著上调，并与LPAR5表达呈正相关。KLF5结合LPAR5的启动子，通过转录促进LPAR5的表达。LPAR5过表达增加了klf5缺失THP-1细胞中M2巨噬细胞的活化。通过磷酸化组学分析，研究了LPAR5的潜在机制，确定了丝裂原活化蛋白激酶激酶激酶7可能是下游效应物。结果表明，LPAR5拮抗剂通过降低M2巨噬细胞活化来减轻新生小鼠气道炎症。KLF5正调控LPAR5的表达，进一步增加巨噬细胞中丝裂原活化蛋白激酶激酶激酶7蛋白的磷酸化。这篇文章强调LPAR5可能作为儿童哮喘的潜在靶点。
{"title":"KLF Transcription Factor 5/Lysophosphatidic Acid Receptor 5 Induced M2 Macrophage Activation and Inflammation by Modulating Phosphorylation of Mitogen-Activated Protein Kinase Kinase Kinase 7 in Pediatric Asthma","authors":"Jing Li , Meixue Chen , Lingling Lu , Yinmiao Wang , Wei Wu , Yanhong Feng","doi":"10.1016/j.ajpath.2025.08.012","DOIUrl":"10.1016/j.ajpath.2025.08.012","url":null,"abstract":"<div><div>Pediatric asthma is a respiratory disease in which M2 macrophages play a critical role. Here, the role and molecular mechanism of lysophosphatidic acid receptor 5 (<em>LPAR5</em>) were investigated in pediatric asthma through <em>in vivo</em> and <em>in vitro</em> experiments. LPAR5 expression was increased in peripheral blood mononuclear cells from children with asthma. In an ovalbumin-induced neonatal asthmatic mouse model, LPAR5 antagonist alleviated airway inflammation by suppressing the release of inflammatory cytokines and inflammatory cell infiltration. Ovalbumin-induced M2 macrophage activation in neonatal mouse lung tissue was suppressed by LPAR5 antagonist, accompanied by decreased YM1 protein (encoded by chitinase 3 like 1) secretion. Differentiated THP-1 cells were stimulated with IL-4 to mimic M2 macrophages <em>in vitro</em>. M2 macrophage activation was reduced by both LPAR5 antagonist or LPAR5 knockdown. Furthermore, KLF transcription factor 5 (<em>KLF5</em>) was significantly up-regulated and positively correlated with LPAR5 expression in peripheral blood mononuclear cells from children with asthma. KLF5 bound to the promoter of LPAR5 and transcriptionally promoted LPAR5 expression. LPAR5 overexpression increased M2 macrophage activation in KLF5-depleted THP-1 cells. The underlying mechanism of LPAR5 was investigated by phosphorylomics analysis, which identified mitogen-activated protein kinase kinase kinase 7 as a possible downstream effector. The results showed that LPAR5 antagonist attenuated airway inflammation in neonatal mice by decreasing M2 macrophage activation. KLF5 positively regulates the expression of LPAR5, which further increased the phosphorylation of mitogen-activated protein kinase kinase kinase 7 protein in macrophages. This article highlights that LPAR5 might serve as a potential target in pediatric asthma.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 12","pages":"Pages 2320-2335"},"PeriodicalIF":3.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ajpath.2025.10.002
Martha B. Furie , Pilar Alcaide , William B. Coleman , Emily H. Essex
{"title":"The American Journal of Pathology and the American Society for Investigative Pathology","authors":"Martha B. Furie , Pilar Alcaide , William B. Coleman , Emily H. Essex","doi":"10.1016/j.ajpath.2025.10.002","DOIUrl":"10.1016/j.ajpath.2025.10.002","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 12","pages":"Pages 2248-2250"},"PeriodicalIF":3.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ajpath.2025.09.003
Daisy Y. Shu
{"title":"The Future of Ocular Pathobiology","authors":"Daisy Y. Shu","doi":"10.1016/j.ajpath.2025.09.003","DOIUrl":"10.1016/j.ajpath.2025.09.003","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 12","pages":"Pages 2254-2257"},"PeriodicalIF":3.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ajpath.2025.08.013
Xin Fu , Lie-Tao Wang , Qian Xu , Hua Yao , Xiao-Xiao Xia , Yucong Wang , Tong-Ling Li , Zhi-Wei Yao , Ji Luo , Guo-Peng Liang , Jing Yang , Qin Wu
Diaphragm dysfunction in sepsis remains a critical challenge in intensive care, yet its underlying mechanisms are poorly understood. This study investigates the role of necroptosis, a recently recognized form of programmed cell death, in sepsis-induced diaphragm dysfunction. A cecal ligation and puncture model in C57BL/6 mice was employed to induce sepsis. Diaphragm function was assessed through ultrasound imaging and pulmonary function testing. Necroptosis markers [receptor-interacting protein kinase (Ripk)-1, Ripk3, and mixed-lineage kinase domain–like protein (Mlkl)] and inflammatory cytokines [Il-6, tumor necrosis factor (Tnf)-α] were quantified using real-time quantitative RT-PCR, Western blot analysis, and enzyme-linked immunosorbent assay. The effect of the necroptosis inhibitor necrostatin-1 (Nec-1) was evaluated in vivo and in vitro. Septic mice exhibited significant diaphragm dysfunction correlated with an elevated expression of necroptosis markers and inflammatory cytokines in diaphragm tissue. Nec-1 treatment not only suppressed necroptosis but also markedly improved diaphragm function and respiratory parameters. In vitro, peritoneal lavage fluid from septic mice induced necroptosis in C2C12 myotubes, an effect mitigated by Nec-1. The findings unveil necroptosis as a key player in sepsis-induced diaphragm dysfunction. A novel mechanism is proposed in which Tnf-α, produced by activated peritoneal macrophages, triggers diaphragm necroptosis. This study not only advances the understanding of the pathophysiology of sepsis but also identifies necroptosis inhibition as a promising therapeutic strategy for preserving diaphragm function in sepsis.
{"title":"Necroptosis Inhibition Preserves Diaphragm Function in Experimental Sepsis","authors":"Xin Fu , Lie-Tao Wang , Qian Xu , Hua Yao , Xiao-Xiao Xia , Yucong Wang , Tong-Ling Li , Zhi-Wei Yao , Ji Luo , Guo-Peng Liang , Jing Yang , Qin Wu","doi":"10.1016/j.ajpath.2025.08.013","DOIUrl":"10.1016/j.ajpath.2025.08.013","url":null,"abstract":"<div><div>Diaphragm dysfunction in sepsis remains a critical challenge in intensive care, yet its underlying mechanisms are poorly understood. This study investigates the role of necroptosis, a recently recognized form of programmed cell death, in sepsis-induced diaphragm dysfunction. A cecal ligation and puncture model in C57BL/6 mice was employed to induce sepsis. Diaphragm function was assessed through ultrasound imaging and pulmonary function testing. Necroptosis markers [receptor-interacting protein kinase (Ripk)-1, Ripk3, and mixed-lineage kinase domain–like protein (Mlkl)] and inflammatory cytokines [Il-6, tumor necrosis factor (Tnf)-α] were quantified using real-time quantitative RT-PCR, Western blot analysis, and enzyme-linked immunosorbent assay. The effect of the necroptosis inhibitor necrostatin-1 (Nec-1) was evaluated <em>in vivo</em> and <em>in vitro</em>. Septic mice exhibited significant diaphragm dysfunction correlated with an elevated expression of necroptosis markers and inflammatory cytokines in diaphragm tissue. Nec-1 treatment not only suppressed necroptosis but also markedly improved diaphragm function and respiratory parameters. <em>In vitro</em>, peritoneal lavage fluid from septic mice induced necroptosis in C2C12 myotubes, an effect mitigated by Nec-1. The findings unveil necroptosis as a key player in sepsis-induced diaphragm dysfunction. A novel mechanism is proposed in which Tnf-α, produced by activated peritoneal macrophages, triggers diaphragm necroptosis. This study not only advances the understanding of the pathophysiology of sepsis but also identifies necroptosis inhibition as a promising therapeutic strategy for preserving diaphragm function in sepsis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 12","pages":"Pages 2373-2386"},"PeriodicalIF":3.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ajpath.2025.10.003
{"title":"CENTENNIAL SERVICE ACKNOWLEDGEMENT","authors":"","doi":"10.1016/j.ajpath.2025.10.003","DOIUrl":"10.1016/j.ajpath.2025.10.003","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 12","pages":"Pages 2512-2514"},"PeriodicalIF":3.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1016/j.ajpath.2025.10.012
Jina Nanayakkara , Xiaojing Yang , Simona Damiani , Tashifa Imtiaz , Xiantao Wang , Dimitrios G. Anastasakis , Girish M. Shah , Kathrin Tyryshkin , Markus Hafner , Xiaolong Yang , Neil Renwick
Molecular regulators of variably aggressive carcinoid tumors are unknown. Since carcinoids have low expression of Yes-associated protein (YAP), it was hypothesized that low YAP expression provides a molecular advantage to carcinoids by preventing YAP from binding its partner, TEA domain transcription factor (TEAD). To test this hypothesis, constitutively active YAP and a TEAD-binding defective form of YAP were overexpressed in lung (H727) and pancreatic (BON1) carcinoid cells. It was found that active YAP overexpression inhibited neuroendocrine markers, morphology, cell proliferation, and anchorage-independent cell growth, whereas TEAD-binding defective YAP recovered these features. Through integrated chromatin immunoprecipitation and RNA sequencing analyses, it was found that YAP-TEAD binding down-regulated neuroendocrine transcription factor genes and up-regulated select transforming growth factor (TGF-β) superfamily and Notch genes related to cell growth. It was concluded that low YAP expression permits neuroendocrine differentiation and growth in carcinoid cells by preventing YAP-TEAD binding and subsequent dysregulation of gene targets. These results identify unknown molecular mechanisms in carcinoid development that may apply to the broader family of neuroendocrine cancers.
{"title":"YAP and TEAD Are Transcriptional Regulators of Neuroendocrine Differentiation and Growth in Carcinoid Cells","authors":"Jina Nanayakkara , Xiaojing Yang , Simona Damiani , Tashifa Imtiaz , Xiantao Wang , Dimitrios G. Anastasakis , Girish M. Shah , Kathrin Tyryshkin , Markus Hafner , Xiaolong Yang , Neil Renwick","doi":"10.1016/j.ajpath.2025.10.012","DOIUrl":"10.1016/j.ajpath.2025.10.012","url":null,"abstract":"<div><div>Molecular regulators of variably aggressive carcinoid tumors are unknown. Since carcinoids have low expression of Yes-associated protein (YAP), it was hypothesized that low YAP expression provides a molecular advantage to carcinoids by preventing YAP from binding its partner, TEA domain transcription factor (TEAD). To test this hypothesis, constitutively active YAP and a TEAD-binding defective form of YAP were overexpressed in lung (H727) and pancreatic (BON1) carcinoid cells. It was found that active YAP overexpression inhibited neuroendocrine markers, morphology, cell proliferation, and anchorage-independent cell growth, whereas TEAD-binding defective YAP recovered these features. Through integrated chromatin immunoprecipitation and RNA sequencing analyses, it was found that YAP-TEAD binding down-regulated neuroendocrine transcription factor genes and up-regulated select transforming growth factor (TGF-β) superfamily and Notch genes related to cell growth. It was concluded that low YAP expression permits neuroendocrine differentiation and growth in carcinoid cells by preventing YAP-TEAD binding and subsequent dysregulation of gene targets. These results identify unknown molecular mechanisms in carcinoid development that may apply to the broader family of neuroendocrine cancers.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 345-358"},"PeriodicalIF":3.6,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.ajpath.2025.10.011
Zijun Wang, Xiaoyue Sun, ZhaoJun Chen, Jingjing Yu, Qing Nie, Zihan Ma, Shuhui Zhou, Ting Li, Hantao Yao, Boxuan Zhao, Yaoting Ji, Li Wang, Minquan Du, Lingxin Zhu
Metabolic disorders and accompanying complications pose considerable risks to systemic organ health. Clinical studies have revealed a significant correlation between nonalcoholic steatohepatitis (NASH) and increased severity of periodontitis. However, directed mechanistic insights remain limited. This study aimed to elucidate the direct impact of NASH on periodontitis progression and to investigate the underlying mechanisms using both in vivo and in vitro models. In mice, a NASH diet induced severe liver damage and steatosis compared with chow-fed controls. Furthermore, NASH significantly exacerbated ligature-induced periodontitis, as evidenced by enhanced alveolar bone loss, inflammatory infiltration, and osteoclast activity. Notably, NASH was associated with elevated macrophage NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in periodontitis relative to lean controls. Mechanistic in vitro experiments revealed that metabolic stimuli, palmitic acid and cholesterol, synergistically promoted NLRP3 inflammasome activation in Porphyromonas gingivalis, P. gingivalis lipopolysaccharide, as well as Escherichia coli lipopolysaccharide-conditioned macrophages. Importantly, macrophage conditioned medium generated with the combination of palmitic acid and cholesterol markedly potentiated osteoclast differentiation and function, as evidenced by enhanced osteoclastogenesis, F-actin ring assembly, and bone resorptive activity in receptor activator of NF-κΒ ligand–stimulated bone marrow–derived macrophages. This study suggests that NASH exacerbates experimental periodontitis by priming periodontal macrophages through the metabolic activation of the NLRP3 inflammasome. These collective data uncover a novel mechanism linking systemic metabolic dysregulation and osteoimmune responses, providing important insights into the comorbidity of inflammatory diseases.
{"title":"Nonalcoholic Steatohepatitis Exacerbates Inflammatory Bone Destruction and Macrophage NLR Family Pyrin Domain-Containing 3 Inflammasome Activation in Ligature-Induced Periodontitis","authors":"Zijun Wang, Xiaoyue Sun, ZhaoJun Chen, Jingjing Yu, Qing Nie, Zihan Ma, Shuhui Zhou, Ting Li, Hantao Yao, Boxuan Zhao, Yaoting Ji, Li Wang, Minquan Du, Lingxin Zhu","doi":"10.1016/j.ajpath.2025.10.011","DOIUrl":"10.1016/j.ajpath.2025.10.011","url":null,"abstract":"<div><div>Metabolic disorders and accompanying complications pose considerable risks to systemic organ health. Clinical studies have revealed a significant correlation between nonalcoholic steatohepatitis (NASH) and increased severity of periodontitis. However, directed mechanistic insights remain limited. This study aimed to elucidate the direct impact of NASH on periodontitis progression and to investigate the underlying mechanisms using both <em>in vivo</em> and <em>in vitro</em> models. In mice, a NASH diet induced severe liver damage and steatosis compared with chow-fed controls. Furthermore, NASH significantly exacerbated ligature-induced periodontitis, as evidenced by enhanced alveolar bone loss, inflammatory infiltration, and osteoclast activity. Notably, NASH was associated with elevated macrophage NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in periodontitis relative to lean controls. Mechanistic <em>in vitro</em> experiments revealed that metabolic stimuli, palmitic acid and cholesterol, synergistically promoted NLRP3 inflammasome activation in <em>Porphyromonas gingivalis</em>, <em>P. gingivalis</em> lipopolysaccharide, as well as <em>Escherichia coli</em> lipopolysaccharide-conditioned macrophages. Importantly, macrophage conditioned medium generated with the combination of palmitic acid and cholesterol markedly potentiated osteoclast differentiation and function, as evidenced by enhanced osteoclastogenesis, F-actin ring assembly, and bone resorptive activity in receptor activator of NF-κΒ ligand–stimulated bone marrow–derived macrophages. This study suggests that NASH exacerbates experimental periodontitis by priming periodontal macrophages through the metabolic activation of the NLRP3 inflammasome. These collective data uncover a novel mechanism linking systemic metabolic dysregulation and osteoimmune responses, providing important insights into the comorbidity of inflammatory diseases.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 288-305"},"PeriodicalIF":3.6,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.ajpath.2025.10.007
César I. Gaspari , Carine Beaupere , Seth Richard , Estanislao Peixoto , Bouchra Lekbaby , Mirko Minini , Branko Dubravcic , Javier Vaquero , Marie Vallette , Ander Arbelaiz , Marion Janona , Corentin Louis , Pauline Le Gall , Cédric Coulouarn , Julieta Marrone , Juan E. Abrahante , Raúl A. Marinelli , Sergio A. Gradilone , Laura Fouassier
Aquaporin-1 (AQP1) is a water channel expressed by cholangiocytes described to modulate cell proliferation and invasion in several cancers. But the role of AQP1 in cholangiocarcinoma (CCA) remains unknown. The aim was to study the function of AQP1 in CCA. AQP1 expression was evaluated in 39 intrahepatic CCA (iCCA) specimens from transcriptomic data. AQP1-knockout in HuCCT1 iCCA cells was achieved by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). Next-generation sequencing (RNA sequencing) was performed to study the consequences of AQP1 inhibition on cell phenotype. Epithelial-mesenchymal transition (EMT), cell migration and proliferation, and signaling pathways were evaluated by live-cell imaging system, quantitative RT-PCR, Western blot, and immunostaining. In vivo experiments were performed using a xenograft CCA model. In human iCCA, low AQP1 expression correlated with reduced overall survival. In vivo, CCA cells depleted for AQP1 displayed a higher tumorigenic potential than control cells. In vitro, RNA-sequencing analysis of AQP1-depleted CCA cells showed signatures of tumor progression, including EMT. Indeed, AQP1-depleted cells showed a cell dispersion phenotype, loss of the junction protein E-cadherin, and higher expression of vimentin and zinc finger E-box binding homeobox 1 (ZEB1), along with stemness traits. Functionally, loss of AQP1 is associated with increased cell migration and proliferation. Moreover, an activation of the insulin-like growth factor 2/insulin-like growth factor 1 receptor/insulin receptor pathway was found in AQP1-depleted CCA cells. The data suggest that AQP1 acts as a tumor suppressor in iCCA.
{"title":"Loss of Aquaporin-1 in Tumor Cells Fosters Intrahepatic Cholangiocarcinoma Progression","authors":"César I. Gaspari , Carine Beaupere , Seth Richard , Estanislao Peixoto , Bouchra Lekbaby , Mirko Minini , Branko Dubravcic , Javier Vaquero , Marie Vallette , Ander Arbelaiz , Marion Janona , Corentin Louis , Pauline Le Gall , Cédric Coulouarn , Julieta Marrone , Juan E. Abrahante , Raúl A. Marinelli , Sergio A. Gradilone , Laura Fouassier","doi":"10.1016/j.ajpath.2025.10.007","DOIUrl":"10.1016/j.ajpath.2025.10.007","url":null,"abstract":"<div><div>Aquaporin-1 (AQP1) is a water channel expressed by cholangiocytes described to modulate cell proliferation and invasion in several cancers. But the role of AQP1 in cholangiocarcinoma (CCA) remains unknown. The aim was to study the function of AQP1 in CCA. AQP1 expression was evaluated in 39 intrahepatic CCA (iCCA) specimens from transcriptomic data. AQP1-knockout in HuCCT1 iCCA cells was achieved by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). Next-generation sequencing (RNA sequencing) was performed to study the consequences of AQP1 inhibition on cell phenotype. Epithelial-mesenchymal transition (EMT), cell migration and proliferation, and signaling pathways were evaluated by live-cell imaging system, quantitative RT-PCR, Western blot, and immunostaining. <em>In vivo</em> experiments were performed using a xenograft CCA model. In human iCCA, low AQP1 expression correlated with reduced overall survival. <em>In vivo</em>, CCA cells depleted for AQP1 displayed a higher tumorigenic potential than control cells. <em>In vitro,</em> RNA-sequencing analysis of AQP1-depleted CCA cells showed signatures of tumor progression, including EMT. Indeed, AQP1-depleted cells showed a cell dispersion phenotype, loss of the junction protein E-cadherin, and higher expression of vimentin and zinc finger E-box binding homeobox 1 (ZEB1), along with stemness traits. Functionally, loss of AQP1 is associated with increased cell migration and proliferation. Moreover, an activation of the insulin-like growth factor 2/insulin-like growth factor 1 receptor/insulin receptor pathway was found in AQP1-depleted CCA cells. The data suggest that AQP1 acts as a tumor suppressor in iCCA.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 428-444"},"PeriodicalIF":3.6,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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