JCI insightPub Date : 2025-09-25DOI: 10.1172/jci.insight.181544
Karenna J Groff, Yini Liang, Christopher Morici, Jinita Modasia, Leena Mehendale, Nishtha Gupta, Angelica D'Amore, Yongho Choe, Mustafa Q Hameed, Alexander Rotenberg, Mustafa Sahin, Christopher J Yuskaitis
{"title":"Focal DEPDC5 loss without disruption to cerebral cortical neuron migration recapitulates DEPDC5-related focal epilepsy.","authors":"Karenna J Groff, Yini Liang, Christopher Morici, Jinita Modasia, Leena Mehendale, Nishtha Gupta, Angelica D'Amore, Yongho Choe, Mustafa Q Hameed, Alexander Rotenberg, Mustafa Sahin, Christopher J Yuskaitis","doi":"10.1172/jci.insight.181544","DOIUrl":"https://doi.org/10.1172/jci.insight.181544","url":null,"abstract":"<p><p>Focal cortical dysplasia (FCD) is a major cause of refractory epilepsy and is associated with pathogenic variants in mTOR pathway genes, including DEPDC5, the most common cause of familial focal epilepsy. The mechanisms of epileptogenesis associated with FCD and hyperactive mTOR signaling remain unclear in DEPDC5-related epilepsy. To test whether DEPDC5 loss leading to seizures require in utero cortical developmental defects or if postnatal neuronal dysfunction of mTORC1 is sufficient to drive seizures, we developed a postnatal focal cortical Depdc5 knockout mouse model. Postnatal day 0-1 Depdc5-floxed mice received unilateral motor cortex injections of either AAV-Cre-GFP or control AAV-GFP. The AAV-Cre-GFP injected hemisphere had decreased DEPDC5 levels with hyperactivation of mTOR that increased with age compared to both the contralateral hemisphere and the AAV-GFP injected mice. Cortical lamination was not disrupted by postnatal DEPDC5 loss. Pathologic hallmarks of FCDs were identified in the Depdc5 knockout hemisphere, including increased SMI-311 neurofilament staining, hypomyelination, astrogliosis, and microglial activation. Mice with postnatal cortical DEPDC5 loss exhibited lower seizure thresholds, increased focal seizures, and increased rates of seizure-induced death compared to control mice. This study demonstrates that postnatal DEPDC5 loss and subsequent mTOR hyperactivation without disruption of cortical migration is sufficient to cause epilepsy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149191","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 : 2025-09-25DOI: 10.1172/jci.insight.199235
Jérémie Prévost, Nikesh Tailor, Geoff Soule, Jonathan Audet, Yvon Deschambault, Robert Vendramelli, Jessica Prado-Smith, Kevin Tierney, Kimberly Azaransky, Darwyn Kobasa, Chad S Clancy, Heinz Feldmann, Kyle Rosenke, David Safronetz
{"title":"CD4+ and CD8+ T-cells are not the main driver of Lassa fever pathogenesis in macaques.","authors":"Jérémie Prévost, Nikesh Tailor, Geoff Soule, Jonathan Audet, Yvon Deschambault, Robert Vendramelli, Jessica Prado-Smith, Kevin Tierney, Kimberly Azaransky, Darwyn Kobasa, Chad S Clancy, Heinz Feldmann, Kyle Rosenke, David Safronetz","doi":"10.1172/jci.insight.199235","DOIUrl":"https://doi.org/10.1172/jci.insight.199235","url":null,"abstract":"<p><p>Empirical data from survivors of Lassa fever and experimental disease modelling efforts, particularly those using mouse models, are at odds with respect to T cell-mediated pathogenesis. In mice, T cells have been shown to be imperative in disease progression and lethality, whereas in humans, an early and robust T cell responses has been associated with survival. Here, we assessed the role of CD4+ and CD8+ T cells on disease progression and severity of Lassa virus infection in a non-human primate model. Using an antibody-mediated T cell depletion strategy prior to and post-inoculation, we were able to examine Lassa virus infection in the absence of specific T cell responses. In animals depleted for either CD4+ or CD8+ T cells, Lassa virus infection remained uniformly lethal, with only a slight delay in disease progression observed in the CD4-depleted group when compared to non-depleted controls. Milder pulmonary pathology was noticed in the absence of CD4+ or CD8+ T cells. Overall, our findings suggest that T cells have a limited impact on the development of Lassa fever in non-human primates.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149194","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 : 2025-09-23DOI: 10.1172/jci.insight.190185
Jan Czogalla, Fabian Hausmann, Simon Lagies, Sydney E Gies, Sabrina Christiansen, Nico Kaiser, Fabian Haas, Yusuke Okabayashi, Dominik Kylies, Smilla Hofmann, Rossana Franzin, Niklas Sabra, Sarah Bouari, Yitian Fang, Gisela Ambagtsheer, Ilka Edenhofer, Silvia Chilla, Anne K Mühlig, Marina Zimmermann, Milagros N Wong, Takashi Yokoo, Oliver Kretz, Maja Lindenmeyer, Florian Grahammer, Martin J Hoogduijn, Ron de Bruin, Malte Kuehl, Sonja Hänzelmann, Bernd Kammerer, Loreto Gesualdo, Stefan Bonn, Robert C Minnee, Tobias B Huber, Victor G Puelles
{"title":"Metabolite-enhanced normothermic machine perfusion improves kidney transplant viability.","authors":"Jan Czogalla, Fabian Hausmann, Simon Lagies, Sydney E Gies, Sabrina Christiansen, Nico Kaiser, Fabian Haas, Yusuke Okabayashi, Dominik Kylies, Smilla Hofmann, Rossana Franzin, Niklas Sabra, Sarah Bouari, Yitian Fang, Gisela Ambagtsheer, Ilka Edenhofer, Silvia Chilla, Anne K Mühlig, Marina Zimmermann, Milagros N Wong, Takashi Yokoo, Oliver Kretz, Maja Lindenmeyer, Florian Grahammer, Martin J Hoogduijn, Ron de Bruin, Malte Kuehl, Sonja Hänzelmann, Bernd Kammerer, Loreto Gesualdo, Stefan Bonn, Robert C Minnee, Tobias B Huber, Victor G Puelles","doi":"10.1172/jci.insight.190185","DOIUrl":"10.1172/jci.insight.190185","url":null,"abstract":"<p><p>Normothermic machine perfusion (NMP) has become a valuable tool to expand the pool of transplantable organs. However, the application of NMP to kidneys presents substantial challenges, mostly due to high variability in the composition of currently used perfusion solutions. Here, we provide a multimodal cross-species cellular atlas of kidney injury associated with NMP using a literature-based consensus buffer. This resource provided a systematic framework that was used to develop a metabolite-enhanced perfusion solution, which protected renal proximal tubular cells, improving cellular viability and transplantation outcomes across species, including human kidneys.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124760","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}
JCI insightPub Date : 2025-09-23DOI: 10.1172/jci.insight.173914
Tabea Bremer, Sripriya Murthy, Sabrina Patzelt, Paul Schilf, Mareike Neumann, Sina Gonther, Jasper Pruessmann, Wiebke Pruessmann, Enno Schmidt, Thomas Rülicke, Christian D Sadik
{"title":"The receptor BLT1 is essential on neutrophils in a mouse model of mucous membrane pemphigoid.","authors":"Tabea Bremer, Sripriya Murthy, Sabrina Patzelt, Paul Schilf, Mareike Neumann, Sina Gonther, Jasper Pruessmann, Wiebke Pruessmann, Enno Schmidt, Thomas Rülicke, Christian D Sadik","doi":"10.1172/jci.insight.173914","DOIUrl":"10.1172/jci.insight.173914","url":null,"abstract":"<p><p>Mucous membrane pemphigoid (MMP) is a mucocutaneous autoimmune blistering disease affecting diverse mucous membranes and the skin with inflammatory blisters and erosions. The pathogenesis of MMP is only poorly understood, but inflammation in MMP is triggered by specific binding of autoantibodies directed to different proteins of the dermal-epidermal/-epithelial junction, subsequently leading to the influx of inflammatory cells, particularly neutrophils, into the dermis. Using the anti-laminin 332 antibody transfer model of MMP, we addressed the molecular mechanisms of neutrophil infiltration and its significance for the eruption of mucocutaneous lesions. Mice deficient in 5-lipoxygenase (Alox5-/-) or in the leukotriene B4 (LTB4) receptor BLT1 (Ltb4r1-/-) were resistant to skin inflammation and exhibited substantially fewer mucosal lesions, with deficiency in either gene compromising the recruitment of neutrophils to the lesion. Furthermore, neutrophil-specific genetic deficiency in Ltb4r1 similarly protected from MMP. Hence, BLT1 was required on neutrophils, and neutrophil recruitment was indispensable for the eruption of lesions in MMP. In line with these findings, the BLT1 inhibitor CP-105,606 ameliorated MMP dose-dependently. Collectively, our results highlight neutrophils and LTB4/BLT1 as key drivers of inflammation in MMP and as promising therapeutic targets.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124789","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}
JCI insightPub Date : 2025-09-23DOI: 10.1172/jci.insight.187023
Rengasamy Palanivel, Jean-Eudes Dazard, Bongsoo Park, Sarah Costantino, Skanda T Moorthy, Armando Vergara-Martel, Elaine Ann Cara, Jonnelle Edwards-Glenn, Shyam Biswal, Lung Chi Chen, Mukesh K Jain, Francesco Paneni, Sanjay Rajagopalan
{"title":"Air pollution modulates brown adipose tissue function through epigenetic regulation by HDAC9 and KDM2B.","authors":"Rengasamy Palanivel, Jean-Eudes Dazard, Bongsoo Park, Sarah Costantino, Skanda T Moorthy, Armando Vergara-Martel, Elaine Ann Cara, Jonnelle Edwards-Glenn, Shyam Biswal, Lung Chi Chen, Mukesh K Jain, Francesco Paneni, Sanjay Rajagopalan","doi":"10.1172/jci.insight.187023","DOIUrl":"https://doi.org/10.1172/jci.insight.187023","url":null,"abstract":"<p><p>Recent experimental and epidemiologic data have strongly associated air pollution in the pathogenesis of insulin resistance and type 2 diabetes mellitus. We explored the effect of inhalational exposure to concentrated ambient particulate matter smaller than 2.5 μm (PM2.5), or filtered air, using a whole-body inhalation system (6 hours/day, 5 days/week) for 24 weeks on metabolism and brown adipose tissue (BAT) function. Mechanistic evaluation of insulin resistance, glucose uptake with 18F-fluorodeoxyglucose positron emission tomography, alongside evaluation for differentially methylated regions, chromatin accessibility, and differential expression of genes was performed. PM2.5 exposure impaired metabolism through changes in key BAT transcriptional programs involved in redox stress, lipid deposition, fibrosis, and altered thermogenesis. Significant differential methylation and widespread chromatin remodeling was noted in BAT with PM2.5. Integrated analysis uncovered a role for the histone deacetylase HDAC9 and histone demethylase KDM2B. The latter demethylates Lys-4 and Lys-36 of histone H3. Specifically, studies using ChIP combined with quantitative PCR confirmed HDAC9 and KDM2B occupancy and reduced H3K36me2 on the promoter of target BAT genes in PM2.5 mice, while Hdac9/Kdm2b knockdown and overexpression increased and reduced BAT metabolism, respectively. Collectively, our results provide insights into air pollution exposure and changes in BAT and metabolism.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124675","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 : 2025-09-23DOI: 10.1172/jci.insight.187002
Qiuyue Chen, Ziyin Zhang, Nanshu Xiang, Li Luo, Xin Dai, Danqing Kang, Lu Yang, Yingzi Zhu, Jiang Chang, Yukai Jing, Na Li, Qianglin Chen, Panpan Jiang, Ju Liu, Yanmei Huang, Heather Miller, Xinyuan Zhou, Fang Zheng, Quan Gong, Chaohong Liu
{"title":"HMGB1 couples LEF1 to regulate B cell immunity.","authors":"Qiuyue Chen, Ziyin Zhang, Nanshu Xiang, Li Luo, Xin Dai, Danqing Kang, Lu Yang, Yingzi Zhu, Jiang Chang, Yukai Jing, Na Li, Qianglin Chen, Panpan Jiang, Ju Liu, Yanmei Huang, Heather Miller, Xinyuan Zhou, Fang Zheng, Quan Gong, Chaohong Liu","doi":"10.1172/jci.insight.187002","DOIUrl":"10.1172/jci.insight.187002","url":null,"abstract":"<p><p>Secreted high mobility group box protein 1 (HMGB1) regulates the adaptive immune response and acts as a biosensor for cells undergoing necrosis, stress, and inflammatory stimulation. However, its role in B cells remains enigmatic. Here, we demonstrate that HMGB1 is critical for peripheral B cell homeostasis and humoral immunity. Conditional deletion of Hmgb1 in B cells led to expanded marginal zone B cells, reduced B1a cells, and impaired antigen-specific antibody responses. Mechanistically, HMGB1 deficiency enhanced proximal and distal B cell receptor (BCR) signaling, probably via increased CD21 expression, which lowered the BCR activation threshold. This phenotype was linked to reduced lymphoid enhancer-binding factor 1 (LEF1) levels, a Wnt-responsive transcription factor, as HMGB1 directly bound the Lef1 promoter to sustain its transcription, thereby repressing Cd21. Furthermore, HMGB1 constrained actin reorganization by suppressing the MST1/DOCK8/WASP axis, which feedback-modulated BCR clustering and signalosome recruitment. Collectively, HMGB1 ensures optimal BCR signaling by transcriptionally and cytoskeletally tuning activation thresholds, highlighting its dual role as a nuclear regulator and cytoskeletal modulator in B cell immunity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124705","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}
JCI insightPub Date : 2025-09-23DOI: 10.1172/jci.insight.193038
Tran H Do, Rachael Bogle, Haihan Zhang, Xianying Xing, Mehrnaz Gharaee-Kermani, Madalina Raducu, Jennifer Fox, Rundong Jiang, Olesya Plazyo, Paul W Harms, Mio Nakamura, Enze Xing, Michel Gilliet, Allison C Billi, J Michelle Kahlenberg, Robert L Modlin, Ozge Uluckan, Lam C Tsoi, Johann E Gudjonsson
{"title":"Th17 cells with regulatory phenotype are the main IL-17F and IL-26 producers in palmoplantar pustulosis.","authors":"Tran H Do, Rachael Bogle, Haihan Zhang, Xianying Xing, Mehrnaz Gharaee-Kermani, Madalina Raducu, Jennifer Fox, Rundong Jiang, Olesya Plazyo, Paul W Harms, Mio Nakamura, Enze Xing, Michel Gilliet, Allison C Billi, J Michelle Kahlenberg, Robert L Modlin, Ozge Uluckan, Lam C Tsoi, Johann E Gudjonsson","doi":"10.1172/jci.insight.193038","DOIUrl":"10.1172/jci.insight.193038","url":null,"abstract":"<p><p>Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder marked by erythematous pustules and desquamation on the palms and soles. While IL-17 pathways are implicated in PPP, IL-17 blockers have shown modest efficacy, underscoring the need for a deeper understanding of IL-17 involvement. To dissect the cellular and spatial architecture of PPP, we performed single-cell RNA-Seq (scRNA-Seq) on lesional, nonlesional, and healthy acral skin to examine cellular composition, transcriptomic profiles, and cell-cell interactions. Unbiased clustering revealed 9 major cell types, including an inflammatory keratinocyte subset enriched in IL-17A/TNF signatures and marked by high IL-36G expression. Within the lymphocyte compartment, we identified a hybrid \"regTh17\" population coexpressing regulatory markers (FOXP3, CTLA4, TIGIT), IL17F, and IL26. This regTh17 subset was distinguished by elevated IL1R1 and CD39, suggesting an IL-1β-driven differentiation. Spatial analyses demonstrated significant neighborhood enrichment of regTh17 cells with IL-36G+ supraspinous keratinocytes. RegTh17 cells were the predominant source of IL-17F and IL-26 signals, whereas keratinocytes were predicted as their main receivers. We further observed regTh17 coexpressing TNFRSF4 (OX40) and TNFRSF18 (GITR) specifically at sites of IL36G+ keratinocyte interactions, implicating these pathways in amplification of the IL-17/IL-36 inflammatory loop. Together, our integrated single-cell and spatial profiling uncovers Th17 plasticity in PPP, identifies a regTh17-keratinocyte interaction, and highlights IL-17F, IL-26, OX40/OX40L, and GITR/GITRL as candidate targets for precision therapies in this challenging disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124671","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}
JCI insightPub Date : 2025-09-23DOI: 10.1172/jci.insight.173742
Ika N Kadariswantiningsih, Issei Okunaga, Kaho Yamasaki, Maulana A Empitu, Hiroyuki Yamada, Shin-Ichi Makino, Akitsu Hotta, Hideo Yagita, Masashi Aizawa, Ryo Koyama-Nasu, Motoko Y Kimura, Narihito Tatsumoto, Katsuhiko Asanuma
{"title":"CCL5 paradoxically regulates glomerular injury by skewing macrophage polarization.","authors":"Ika N Kadariswantiningsih, Issei Okunaga, Kaho Yamasaki, Maulana A Empitu, Hiroyuki Yamada, Shin-Ichi Makino, Akitsu Hotta, Hideo Yagita, Masashi Aizawa, Ryo Koyama-Nasu, Motoko Y Kimura, Narihito Tatsumoto, Katsuhiko Asanuma","doi":"10.1172/jci.insight.173742","DOIUrl":"https://doi.org/10.1172/jci.insight.173742","url":null,"abstract":"<p><p>Glomerular inflammation and podocyte loss are the hallmarks of chronic kidney disease (CKD) progression. Understanding how podocytes and their microenvironment regulate inflammation is critical for developing effective therapies. In this study, we identified C-C chemokine ligand 5 (CCL5) as an inflammatory mediator elevated in injured podocytes, based on analyses of both human kidney biopsies and mouse models of CKD. We discovered that CCL5 exerts paradoxical effects in nephropathy: while it protects podocytes in vitro, it exacerbates glomerular injury in vivo. Recombinant CCL5 and podocyte-specific CCL5 overexpression promoted cell survival and reduced apoptosis in cultured podocytes. However, in Adriamycin-induced nephropathy, CCL5 worsened glomerular injury, increasing proteinuria, glomerulosclerosis, and podocyte loss. Bone marrow (BM) transplantation experiments revealed that CCL5 in BM-derived cells-not kidney-resident cells-drove disease progression. CCL5 deficiency in BM-derived cells conferred protection by increasing reparative M2 macrophages, whereas endogenous CCL5 promoted M1 polarization, inhibited M2 differentiation, and triggered M2-to-M1 transition. These findings demonstrate that while CCL5 supports podocyte survival, its expression in BM-derived cells promotes inflammatory macrophage phenotypes and glomerular injury. The harmful immune effects of CCL5 in BM-derived cells outweigh its podocyte-protective role, highlighting the importance of cell-targeted strategies to mitigate kidney damage.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130875","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 : 2025-09-23DOI: 10.1172/jci.insight.194227
Brian Cheng, Tristan D Tibbe, Siyuan Yao, Megan Wei, Zeriel Y Wong, Taylor Torgerson, Richard Chiu, Aanchal S Kasargod, Kojiro Nakamura, Monica Cappelletti, Myung Sim, Douglas G Farmer, Fady Kaldas, Jerzy W Kupiec-Weglinski, Kenneth J Dery
{"title":"Posttranscriptional control of hepatic CEACAM1 3'UTR by human antigen R (HuR) mitigates sterile liver inflammation.","authors":"Brian Cheng, Tristan D Tibbe, Siyuan Yao, Megan Wei, Zeriel Y Wong, Taylor Torgerson, Richard Chiu, Aanchal S Kasargod, Kojiro Nakamura, Monica Cappelletti, Myung Sim, Douglas G Farmer, Fady Kaldas, Jerzy W Kupiec-Weglinski, Kenneth J Dery","doi":"10.1172/jci.insight.194227","DOIUrl":"10.1172/jci.insight.194227","url":null,"abstract":"<p><p>Hepatic ischemia-reperfusion injury (IRI) disrupts cellular signaling pathways and contributes to early allograft dysfunction (EAD) in orthotopic liver transplantation (OLT). In this study, we found that the hepatic RNA binding protein Human Antigen R (HuR) regulated the 3' untranslated region (UTR) of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (Ceacam1) following ischemic stress. Hepatocyte-specific preinjury HuR-null mice exhibited elevated LDH-5 isoenzyme activity and reduced Ceacam1-S expression, reflecting tissue-specific injury. In situ hybridization demonstrated that the stability of Ceacam1 mRNA depended on HuR. Luciferase assays identified Ceacam1 3'UTR cis-elements responsive to high oxygen tension. HuR-targeting short-activating RNAs (saRNAs) preferentially induced the alternative splicing of Ceacam1-S. Antisense oligos directed to the Ceacam1 3'UTR protected WT mice against acute liver injury. In the clinical arm, increased HuR and CEACAM1 expression were associated with reduced proinflammatory phenotype and a lower incidence of EAD in patients with OLT (n = 164). Human discarded livers with elevated ELAVL1/CEACAM1 levels correlated with improved tissue homeostasis. These findings suggest that HuR regulation of Ceacam1 represents a key determinant of donor tissue quality and offers a potential target for future therapeutic strategies in OLT recipients.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124758","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}
{"title":"Nf2/FGFR1/AKT axis directs cranial neural crest-derived skull morphogenesis via collagen synthesis and trafficking.","authors":"Yuping Huang, Junguang Liao, Panpan Shen, Yiliang He, Fuju Sun, Qi Zhang, Changlin Zheng, Xingen Zhang, Haibo Li, Guiqian Chen","doi":"10.1172/jci.insight.191112","DOIUrl":"10.1172/jci.insight.191112","url":null,"abstract":"<p><p>Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molecular scaffolds coordinating these processes remain incompletely defined. Here, we identify neurofibromin 2 (Nf2) as a critical regulator to direct CNC-derived skull morphogenesis. Genetic ablation of Nf2 in murine CNCs causes severe craniofacial anomalies, featuring declined proliferation and increased apoptosis in osteoprogenitors, impaired type I collagen biosynthesis and trafficking, and aberrant osteogenic mineralization. Mechanistically, we uncover that Nf2 serves as a molecular linker that individually interacts with FGF receptor 1 (FGFR1) and Akt through spatially segregated phosphor-sites, and structural modeling and mutagenesis identified Ser10 and Thr230 as essential residues, with Thr230 mutation selectively ablating Akt binding while preserving FGFR1 association. Strikingly, Akt inhibition phenocopied Nf2 deficiency, reducing collagen production and Nf2 phosphorylation, whereas phospho-mimetic Nf2 (T230D) rescued CNC-derived osteogenic defects in Nf2-mutant animals. Our findings underscore the physiological significance of Nf2 as a phosphorylation-operated scaffold licensing the FGFR1/AKT axis to regulate collagen type I biogenesis and trafficking, ensuring normal CNC-derived osteogenesis and craniofacial bone development, thus exposing the Nf2/FGFR1/AKT signaling axis as a therapeutic target and promising advancements in treatment of craniofacial anomalies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 18","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124691","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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