JCI insightPub Date : 2025-05-22DOI: 10.1172/jci.insight.179246
Rohan Gupta, Irina Bunea, Bruno Alvisio, Francesca Barone, Rishabh Gupta, Dara Baker, Haohua Qian, Elena Daniele, Casey G Contreary, Jair Montford, Ruchi Sharma, Arvydas Maminishkis, Mandeep S Singh, Maria Teresa Magone De Quadros Costa, Amir H Kashani, Juan Amaral, Kapil Bharti
{"title":"iPSC-RPE patch restores photoreceptors and regenerates choriocapillaris in a pig retinal degeneration model.","authors":"Rohan Gupta, Irina Bunea, Bruno Alvisio, Francesca Barone, Rishabh Gupta, Dara Baker, Haohua Qian, Elena Daniele, Casey G Contreary, Jair Montford, Ruchi Sharma, Arvydas Maminishkis, Mandeep S Singh, Maria Teresa Magone De Quadros Costa, Amir H Kashani, Juan Amaral, Kapil Bharti","doi":"10.1172/jci.insight.179246","DOIUrl":"10.1172/jci.insight.179246","url":null,"abstract":"<p><p>Dry age-related macular degeneration (AMD) is a leading cause of untreatable vision loss. In advanced cases, retinal pigment epithelium (RPE) cell loss occurs alongside photoreceptor and choriocapillaris degeneration. We hypothesized that an RPE-patch would mitigate photoreceptor and choriocapillaris degeneration to restore vision. An induced pluripotent stem cell-derived RPE (iRPE) patch was developed using a clinically compatible manufacturing process by maturing iRPE cells on a biodegradable poly(lactic-co-glycolic acid) (PLGA) scaffold. To compare outcomes, we developed a surgical procedure for immediate sequential delivery of PLGA-iRPE and/or PLGA-only patches in the subretinal space of a pig model of laser-induced outer retinal degeneration. Deep learning algorithm-based optical coherence tomography (OCT) image segmentation verified preservation of the photoreceptors over the areas of PLGA-iRPE-transplanted retina and not in laser-injured or PLGA-only-transplanted retina. Adaptive optics imaging of individual cone photoreceptors further supported this finding. OCT-angiography revealed choriocapillaris regeneration in PLGA-iRPE- and not in PLGA-only-transplanted retinas. Our data, obtained using clinically relevant techniques, verified that PLGA-iRPE supports photoreceptor survival and regenerates choriocapillaris in a laser-injured pig retina. Sequential delivery of two 8 mm2 transplants allows for testing of surgical feasibility and safety of the double dose. This work allows one surgery to treat larger and noncontiguous retinal degeneration areas.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 10","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119415","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 : 2025-05-22DOI: 10.1172/jci.insight.191059
Elisabeth Fließer, Katharina Jandl, Shiau-Haln Chen, Mei-Tzu Wang, Jonas C Schupp, Wolfgang M Kuebler, Andrew H Baker, Grazyna Kwapiszewska
{"title":"Transcriptional signatures of endothelial cells shape immune responses in cardiopulmonary health and disease.","authors":"Elisabeth Fließer, Katharina Jandl, Shiau-Haln Chen, Mei-Tzu Wang, Jonas C Schupp, Wolfgang M Kuebler, Andrew H Baker, Grazyna Kwapiszewska","doi":"10.1172/jci.insight.191059","DOIUrl":"10.1172/jci.insight.191059","url":null,"abstract":"<p><p>The cardiopulmonary vasculature and its associated endothelial cells (ECs) play an essential role in sustaining life by ensuring the delivery of oxygen and nutrients. Beyond these foundational functions, ECs serve as key regulators of immune responses. Recent advances in single-cell RNA sequencing have revealed that the cardiopulmonary vasculature is composed of diverse EC subpopulations, some of which exhibit specialized immunomodulatory properties. Evidence for immunomodulation includes distinct expression profiles associated with antigen presentation, cytokine secretion, immune cell recruitment, translocation, and clearance - functions critical for maintaining homeostasis in the heart and lungs. In cardiopulmonary diseases, ECs undergo substantial transcriptional reprogramming, leading to a shift from homeostasis to an activated state marked by heightened immunomodulatory activity. This transformation has highlighted the critical role for ECs in disease pathogenesis and their potential as future therapy targets. This Review emphasizes the diverse functions of ECs in the heart and lungs, particularly adaptive and maladaptive immunoregulatory roles in cardiopulmonary health and disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 10","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119420","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 : 2025-05-22eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.153601
Jin Cheng, Liyang Zhao, Sahra Bodo, Prashanth Kb Nagesh, Rajvir Singh, Adam O Michel, Regina Feldman, Zhigang Zhang, Simon Powell, Zvi Fuks, Richard Kolesnick
{"title":"Radiosensitizing the SUMO stress response intensifies single-dose radiotherapy tumor cure.","authors":"Jin Cheng, Liyang Zhao, Sahra Bodo, Prashanth Kb Nagesh, Rajvir Singh, Adam O Michel, Regina Feldman, Zhigang Zhang, Simon Powell, Zvi Fuks, Richard Kolesnick","doi":"10.1172/jci.insight.153601","DOIUrl":"10.1172/jci.insight.153601","url":null,"abstract":"<p><p>Single-dose radiotherapy (SDRT) is a highly curative modality that may transform radiotherapy practice. Unfortunately, only ~50% of oligometastatic lesions are SDRT treatable due to adjacent radiosensitive normal organs at risk. Here, we address the extent to which an antiangiogenic drug, VEGFR2-antagonist DC101, radiosensitizes SDRT using murine MCA/129 fibrosarcomas and Lewis lung carcinomas, which display a dose range for SDRT lesional eradication virtually identical to that employed clinically (10-30 Gy). SDRT induces unique tumor cure, stimulating rapid endothelial acid sphingomyelinase (ASMase)/ceramide signaling that yields marked vasoconstriction and perfusion defects in tumor xenografts and human oligometastases. Ensuing tumor parenchymal oxidative damage initiates a SUMO stress response (SSR), which inactivates multiple homologous recombination repair enzymes, radiosensitizing all tumor types. While VEGF inhibits neo-angiogenic ASMase, optimal radiosensitization occurs only upon antiangiogenic drug delivery at ~1 hour preceding SDRT. Obeying these principles, we find DC101 radiosensitizes SSR, DNA double-strand break unrepair, and tumor cure by 4-8 Gy at all clinically relevant doses. Critically, DC101 fails to sensitize small intestinal endothelial injury or lethality from the gastrointestinal-acute radiation syndrome. Whereas normal tissues appear not to be under VEGF regulation nor sensitized by our approach, its application might render many currently intractable oligometastatic lesions susceptible to SDRT eradication.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127310","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 : 2025-05-20eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.188724
Romain Vaineau, Raphaël Jeger-Madiot, Samir Ali-Moussa, Laura Prudhomme, Hippolyte Debarnot, Nicolas Coatnoan, Johanna Dubois, Marie Binvignat, Hélène Vantomme, Bruno Gouritin, Gwladys Fourcade, Paul Engeroff, Aude Belbézier, Romain Luscan, Françoise Denoyelle, Roberta Lorenzon, Claire Ribet, Michelle Rosenzwajg, Bertrand Bellier, David Klatzmann, Nicolas Tchitchek, Stéphanie Graff-Dubois
{"title":"IL-1β signaling modulates T follicular helper and regulatory cells in human lymphoid tissues.","authors":"Romain Vaineau, Raphaël Jeger-Madiot, Samir Ali-Moussa, Laura Prudhomme, Hippolyte Debarnot, Nicolas Coatnoan, Johanna Dubois, Marie Binvignat, Hélène Vantomme, Bruno Gouritin, Gwladys Fourcade, Paul Engeroff, Aude Belbézier, Romain Luscan, Françoise Denoyelle, Roberta Lorenzon, Claire Ribet, Michelle Rosenzwajg, Bertrand Bellier, David Klatzmann, Nicolas Tchitchek, Stéphanie Graff-Dubois","doi":"10.1172/jci.insight.188724","DOIUrl":"10.1172/jci.insight.188724","url":null,"abstract":"<p><p>Dysregulation of T follicular helper (Tfh) and T follicular regulatory (Tfr) cell homeostasis in germinal centers (GCs) can lead to antibody-mediated autoimmunity. While IL-1β modulates the GC response via IL-1R1 and IL-1R2 receptors on follicular T cells in animal models, its role in humans remains unclear. We analyzed Tfh and Tfr phenotypes in human secondary lymphoid organs (tonsils, spleen, and mesenteric lymph nodes) using flow cytometry, single-cell transcriptomics, and in vitro culture, comparing findings with samples from autoimmune patients. We observed organ-specific Tfh/Tfr phenotypes according to activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 expression promoted a unique activated Tfr subset with Treg and GC-Tfh features. IL-1β signaling via IL-1R1 enhanced follicular T cell activation and Tfh-to-Tfr differentiation, while IL-1β inhibition upregulated IL-1R1, indicating a tightly regulated process. In autoimmune patients, high IL-1β and circulating Tfr levels correlated with increased autoantibody production, linking inflammation, IL-1β signaling, and Tfr/Tfh balance. Our findings highlight the critical role of IL-1β in follicular T cell activation and suggest that targeting IL-1β signaling in Tfh and Tfr cells could be a promising strategy for treating antibody-mediated autoimmune diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110595","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 : 2025-05-20eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.188062
Hamed Khedmatgozar, Sayanika Dutta, Michael Dominguez, Murugananthkumar Raju, Girijesh Kumar Patel, Daniel Latour, Melanie K Johnson, Mohamed Fokar, Irfan Warraich, Allan Haynes, Barry J Maurer, Werner de Riese, Luis Brandi, Robert J Matusik, Srinivas Nandana, Manisha Tripathi
{"title":"TIAM1 drives prostatic branching phenotype and is a potential therapeutic target for benign prostatic hyperplasia.","authors":"Hamed Khedmatgozar, Sayanika Dutta, Michael Dominguez, Murugananthkumar Raju, Girijesh Kumar Patel, Daniel Latour, Melanie K Johnson, Mohamed Fokar, Irfan Warraich, Allan Haynes, Barry J Maurer, Werner de Riese, Luis Brandi, Robert J Matusik, Srinivas Nandana, Manisha Tripathi","doi":"10.1172/jci.insight.188062","DOIUrl":"10.1172/jci.insight.188062","url":null,"abstract":"<p><p>Benign prostatic hyperplasia (BPH) is the most common urologic condition in elderly men, characterized by the reactivation of developmental programs such as prostatic budding and branching. However, the molecular mechanisms underlying this reactivation in BPH remain unclear. In this study, we identified T-lymphoma invasion and metastasis-inducing protein-1 (TIAM1) as a critical regulator of prostatic budding and branching. By generating an unbiased BPH transcriptomic signature from patient datasets, we discovered an upregulation of TIAM1, which was subsequently validated at the protein level. Functional assays using organoid cultures derived from human prostatic cell lines revealed that TIAM1 is essential for prostatic budding and branching. Additionally, the BPH transcriptomic signature identified NSC23766, a small molecule inhibitor of TIAM1/RAC1 signaling, as a therapeutic proof-of-concept agent for BPH. Genetic knockdown of TIAM1 in human prostatic cell lines markedly reduced organoid branching, an effect mirrored by administration of NSC23766. The translational relevance of these findings is underscored by the growth inhibition observed in patient-derived BPH organoids treated with NSC23766. In conclusion, our findings identify TIAM1 as a key driver of prostatic branching and growth, and they suggest that targeting TIAM1/RAC1 signaling could be a promising therapeutic strategy for BPH.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110641","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 : 2025-05-20DOI: 10.1172/jci.insight.189295
Noely Evangelista Ferreira, Michael G Berg, Antonio C da Costa, Mary A Rodgers, Esper G Kallas, Cassia G Terrasani Silveira, Mateus Vailant Thomazella, Ana Carolina Soares de Oliveira, Layla Honorato, Heuder Go Paião, Renan Barros Domingues, Carlos Senne, Marina F Côrtes, Tania R Tozetto-Mendoza, Hélio R Gomes, Maria Laura Mariano Matos, Geovani de Oliveria Ribeiro, Steven S Witkin, Gavin A Cloherty, Maria Cassia Mendes-Correa
{"title":"Metagenomic detection of central nervous system infections missed by conventional testing.","authors":"Noely Evangelista Ferreira, Michael G Berg, Antonio C da Costa, Mary A Rodgers, Esper G Kallas, Cassia G Terrasani Silveira, Mateus Vailant Thomazella, Ana Carolina Soares de Oliveira, Layla Honorato, Heuder Go Paião, Renan Barros Domingues, Carlos Senne, Marina F Côrtes, Tania R Tozetto-Mendoza, Hélio R Gomes, Maria Laura Mariano Matos, Geovani de Oliveria Ribeiro, Steven S Witkin, Gavin A Cloherty, Maria Cassia Mendes-Correa","doi":"10.1172/jci.insight.189295","DOIUrl":"https://doi.org/10.1172/jci.insight.189295","url":null,"abstract":"<p><p>Community-acquired infectious meningoencephalitis is associated with high rates of mortality and morbidity, compounded by limited access to diagnostic resources. The current study assessed acute central nervous system (CNS) infections in patients with meningoencephalitis enrolled in a hospital-based diagnostic surveillance study in São Paulo, Brazil. Cerebrospinal fluid (CSF) was collected from 600 subjects between March 2018 and November 2019 and initially screened for a broad range of pathogens according to a local diagnostic algorithm. Standard microbiological and molecular diagnostic methods were applied. Metagenomic sequencing was used as a complementary approach to investigating etiology in cases where no pathogen was initially identified. Standard testing identified infectious etiologies in 292 cases (48.6%), with 227 (77.7%) confirmed as viral infections, predominantly caused by enteroviruses (n=144) and herpesviruses (n=40). Non-viral agents were identified in 65 cases (22.3%). Metagenomic sequencing (mNGS) of 279 out of 308 undiagnosed cases revealed several additional potential etiologies, including Parvovirus B19, Toxoplasma gondii, Picobirnavirus, other enterovirus species and Vesivirus, the latter being associated with CNS infection for the first time. These findings underscore the complexity of CNS infections and highlight the potential of metagenomics to improve diagnostic accuracy, inform treatment strategies, and support efforts to address future pandemics.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110609","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 : 2025-05-20eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.172370
Fabian Braun, Amrei M Mandel, Linda Blomberg, Milagros N Wong, Georgia Chatzinikolaou, David H Meyer, Anna Reinelt, Viji Nair, Roman Akbar-Haase, Phillip J McCown, Fabian Haas, He Chen, Mahdieh Rahmatollahi, Damian Fermin, Robin Ebbestad, Gisela G Slaats, Tillmann Bork, Christoph Schell, Sybille Koehler, Paul T Brinkkoetter, Maja T Lindenmeyer, Clemens D Cohen, Martin Kann, David Unnersjö-Jess, Wilhelm Bloch, Matthew G Sampson, Martijn Et Dollé, Victor G Puelles, Matthias Kretzler, George A Garinis, Tobias B Huber, Bernhard Schermer, Thomas Benzing, Björn Schumacher, Christine E Kurschat
{"title":"Loss of genome maintenance is linked to mTOR complex 1 signaling and accelerates podocyte damage.","authors":"Fabian Braun, Amrei M Mandel, Linda Blomberg, Milagros N Wong, Georgia Chatzinikolaou, David H Meyer, Anna Reinelt, Viji Nair, Roman Akbar-Haase, Phillip J McCown, Fabian Haas, He Chen, Mahdieh Rahmatollahi, Damian Fermin, Robin Ebbestad, Gisela G Slaats, Tillmann Bork, Christoph Schell, Sybille Koehler, Paul T Brinkkoetter, Maja T Lindenmeyer, Clemens D Cohen, Martin Kann, David Unnersjö-Jess, Wilhelm Bloch, Matthew G Sampson, Martijn Et Dollé, Victor G Puelles, Matthias Kretzler, George A Garinis, Tobias B Huber, Bernhard Schermer, Thomas Benzing, Björn Schumacher, Christine E Kurschat","doi":"10.1172/jci.insight.172370","DOIUrl":"10.1172/jci.insight.172370","url":null,"abstract":"<p><p>DNA repair is essential for preserving genome integrity. Podocytes, postmitotic epithelial cells of the kidney filtration unit, bear limited regenerative capacity, yet their survival is indispensable for kidney health. Podocyte loss is a hallmark of the aging process and of many diseases, but the underlying factors remain unclear. We investigated the consequences of DNA damage in a podocyte-specific knockout mouse model for DNA excision repair protein Ercc1 and in cultured podocytes under genomic stress. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages and patients with minimal change disease and focal segmental glomerulosclerosis. Ercc1 knockout resulted in accumulation of DNA damage and ensuing albuminuria and kidney disease. Podocytes reacted to genomic stress by activating mTOR complex 1 (mTORC1) signaling in vitro and in vivo. This was abrogated by inhibiting DNA damage signaling through DNA-dependent protein kinase (DNA-PK) and ataxia teleangiectasia mutated (ATM) kinases, and inhibition of mTORC1 modulated the development of glomerulosclerosis. Perturbed DNA repair gene expression and genomic stress in podocytes were also detected in focal segmental glomerulosclerosis. Beyond that, DNA damage signaling occurred in podocytes of healthy aging mice and humans. We provide evidence that genome maintenance in podocytes is linked to the mTORC1 pathway and is involved in the aging process as well as the development of glomerulosclerosis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110605","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 : 2025-05-15eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.186646
Yuening Li, Elizabeth H Gray, Rosie Ross, Irene Zebochin, Amy Lock, Laura Fedele, Louisa Janice Kamajaya, Rebecca J Marrow, Sarah Ryan, Pascal Röderer, Oliver Brüstle, Susan John, Franziska Denk, Leonie S Taams
{"title":"Rheumatoid arthritis synovial fluid induces JAK-dependent intracellular activation of human sensory neurons.","authors":"Yuening Li, Elizabeth H Gray, Rosie Ross, Irene Zebochin, Amy Lock, Laura Fedele, Louisa Janice Kamajaya, Rebecca J Marrow, Sarah Ryan, Pascal Röderer, Oliver Brüstle, Susan John, Franziska Denk, Leonie S Taams","doi":"10.1172/jci.insight.186646","DOIUrl":"10.1172/jci.insight.186646","url":null,"abstract":"<p><p>JAK inhibitors (JAKi) are widely used antiinflammatory drugs. Recent data suggest that JAKi have superior effects on pain reduction in rheumatoid arthritis (RA). However, the underlying mechanisms for this observation are not fully understood. We investigated whether JAKi can act directly on human sensory neurons. We analyzed RNA-seq datasets of sensory neurons and found that they expressed JAK1 and STAT3. Addition of cell-free RA synovial fluid to human induced pluripotent stem cell-derived (iPSC-derived) sensory neurons led to phosphorylation of STAT3 (pSTAT3), which was completely blocked by the JAKi tofacitinib. Compared with paired serum, RA synovial fluid was enriched for the STAT3 signalling cytokines IL-6, IL-11, LIF, IFN-α, and IFN-β, with their requisite receptors present in peripheral nerves postmortem. Accordingly, these recombinant cytokines induced pSTAT3 in iPSC-derived sensory neurons. Furthermore, IL-6 + sIL-6R and LIF upregulated expression of pain-relevant genes with STAT3-binding sites, an effect that was blocked by tofacitinib. LIF also induced neuronal sensitization, highlighting this molecule as a putative pain mediator. Finally, over time, tofacitinib reduced the firing rate of sensory neurons stimulated with RA synovial fluid. Together, these data indicate that JAKi can act directly on human sensory neurons, providing a potential mechanistic explanation for their suggested superior analgesic properties.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078144","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 : 2025-05-13DOI: 10.1172/jci.insight.175917
Ameer Y Taha, Qing Shen, Yurika Otoki, Nuanyi Liang, Kelley T Patten, Anthony E Valenzuela, Christopher D Wallis, Douglas J Rowland, Abhijit J Chaudhari, Keith J Bein, Anthony S Wexler, Lee-Way Jin, Brittany N Dugger, Danielle J Harvey, Pamela J Lein
{"title":"Air pollution and Alzheimer disease phenotype deplete esterified pro-resolving lipid mediator reserves in the brain.","authors":"Ameer Y Taha, Qing Shen, Yurika Otoki, Nuanyi Liang, Kelley T Patten, Anthony E Valenzuela, Christopher D Wallis, Douglas J Rowland, Abhijit J Chaudhari, Keith J Bein, Anthony S Wexler, Lee-Way Jin, Brittany N Dugger, Danielle J Harvey, Pamela J Lein","doi":"10.1172/jci.insight.175917","DOIUrl":"https://doi.org/10.1172/jci.insight.175917","url":null,"abstract":"<p><strong>Background: </strong>Traffic-related air pollution (TRAP) is a risk factor for Alzheimer disease (AD), where unresolved brain inflammation has been linked to deficits in the levels of free lipid mediators that enable the resolution of inflammation. It is unknown whether these deficits are due to reductions in esterified lipid pools, the main source of free bioactive pro-resolving lipids in the brain, and whether they are related AD pathophysiology.</p><p><strong>Methods: </strong>This unknown was tested by measuring brain esterified lipid mediators and pathogenic markers of AD in TgF344-AD and wildtype (WT) male and female rats exposed to filtered air or TRAP for 14 months, and in human postmortem pre-frontal cortex of individuals with or without AD.</p><p><strong>Results: </strong>Significant reductions in pro-resolving lipid mediators esterified to neutral lipids and/or phospholipids were seen in AD and TRAP-exposed female rats, where levels were associated with inflammation, synaptic loss and impaired glucose metabolism. Lower esterified pro-resolving lipid mediator concentrations were associated with older age in pre-frontal cortex of humans with AD.</p><p><strong>Conclusion: </strong>Impaired resolution in AD is due to depletion of esterified pro-resolving lipid pools that supply the brain with free bioactive mediators involved in inflammation resolution. TRAP exposure alters the same esterified resolution pathways, reflecting convergent mechanisms underlying AD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036044","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 : 2025-05-13eCollection Date: 2025-06-23DOI: 10.1172/jci.insight.191555
Kevin F Dowling, Shohini K Ghosh-Choudhary, Neil Carleton, Kathleen Prigg, Richard A Steinman
{"title":"Development and evaluation of a symposium model for building physician-scientist skills, connections, and persistence.","authors":"Kevin F Dowling, Shohini K Ghosh-Choudhary, Neil Carleton, Kathleen Prigg, Richard A Steinman","doi":"10.1172/jci.insight.191555","DOIUrl":"10.1172/jci.insight.191555","url":null,"abstract":"<p><p>High rates of physician-scientist attrition from the investigative workforce remain a significant problem despite the development of dedicated programs and initiatives designed to address the unique challenges faced by physician-scientists. However, many of these efforts are restricted to single career stages of physician-scientist training or to a single medical specialty, which may limit opportunities for beneficial vertical and horizontal mentorship regarding overcoming common career obstacles. Here, we outline the development of a physician-scientist symposium to break down silos and enable productive interactions between physician-scientists across career/training stages, academic and scientific disciplines, and medical specialties. Participants were (a) mixed in small-group problem-based discussions, (b) participated in a cross-specialty keynote panel on overcoming barriers in a physician-scientist career, and (c) took part in skill-building workshops. Attendees indicated that they fostered new connections, developed new skills to overcome career challenges, and increased their commitment to persevering in a career as a physician-scientist. Positive evaluations were not dependent on attendee career/training stage or gender. We suggest these elements of the symposium curriculum may be easily adapted for inclusion in a wide variety of physician-scientist training formats.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015901","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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