JCI insight最新文献

{"title":"Loss of GATA2 Promotes Invasion and Predicts Cancer Recurrence and Survival in Uterine Serous Carcinoma.","authors":"Usha S Polaki, Trey E Gilpin, Apoorva T Patil, Emily Chiu, Ruth Baker, Peng Liu, Tatiana S Pavletich, Morteza Seifi, Paula M Mañán-Mejías, Jordan Morrissey, Jenna Port, Rene Welch Schwartz, Irene M Ong, Dina El-Rayes, Mahmoud A Khalifa, Pei Hui, Vanessa L Horner, María Virumbrales-Muñoz, Britt K Erickson, Lisa Barroilhet, Stephanie M McGregor, Emery H Bresnick, Daniel R Matson","doi":"10.1172/jci.insight.187073","DOIUrl":"https://doi.org/10.1172/jci.insight.187073","url":null,"abstract":"<p><strong>Background: </strong>A priori knowledge of recurrence risk in patients with non-metastatic (FIGO stage I) uterine serous carcinoma (USC) would enable a risk-stratified approach to the use of adjuvant chemotherapy. This would greatly reduce treatment-related morbidity and be predicted to improve survival.</p><p><strong>Methods: </strong>GATA2 expression was scored by immunohistochemistry (IHC) across a retrospective multi-institutional cohort of 195 primary USCs. Associations between GATA2 levels and clinicopathologic metrics were evaluated using Student's t-test, Fisher's exact test, Kaplan-Meier method, and Cox proportional hazards ratio. Invasion in patient-derived USC cells was assessed by Student's t-test. RNA-seq, anti-GATA2 ChIP-seq, and confirmatory western blotting enabled identification of GATA2 targets.</p><p><strong>Results: </strong>Patients with FIGO stage I GATA2high USCs had 100% recurrence-free and 100% cancer related survival, which was significantly better than patients with GATA2low USCs. In patients for whom adjuvant chemotherapy was omitted, patients with GATA2high USC had 100% recurrence free 5-year survival compared to 60% recurrence free survival in patients with GATA2low USC. Depletion of GATA2 in patient-derived USC cells increased invasion in vitro.</p><p><strong>Conclusions: </strong>Routine GATA2 IHC identifies 33% of FIGO stage I USC patients who have a greatly reduced risk of post-hysterectomy USC recurrence. Our results suggest that a GATA2 guided personalized medicine approach could be rapidly implemented in most hospital settings, would reduce treatment-related morbidity, and likely improve outcomes in USC patients.</p><p><strong>Funding: </strong>NIH grants R01 DK068634, P30 CA014520, S10 OD023526, K08 DK127244, T32 HL007899, the UW-Madison Department of Pathology and Laboratory Medicine, the UW-Madison Centennial Scholars Program, the Diane Lindstrom Foundation, the American Cancer Society, the V Foundation, The Hartwell Foundation, and the UMN Department of Obstetrics, Gynecology, and Women's Health.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752810","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}

{"title":"Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection.","authors":"Pei-Suen Tsou, Ramadan A Ali, Chenyang Lu, Gautam Sule, Carmelo Carmona-Rivera, Serena Lucotti, Yuzo Ikari, Qi Wu, Phillip Campbell, Mikel Gurrea-Rubio, Kohei Maeda, Sharon E Fox, William D Brodie, Megan N Mattichak, Caroline Foster, Ajay Tambralli, Srilakshmi Yalavarthi, M Asif Amin, Katarina Kmetova, Bruna Mazetto Fonseca, Emily Chong, Yu Zuo, Michael Maile, Luisa Imberti, Arnaldo Caruso, Francesca Caccuri, Virginia Quaresima, Alessandra Sottini, Douglas B Kuhns, Danielle L Fink, Riccardo Castagnoli, Ottavia Delmonte, Heather Kenney, Yu Zhang, Mary Magliocco, Helen C Su, Luigi D Notarangelo, Rachel L Zemans, Yang Mao-Draayer, Irina Matei, Mirella Salvatore, David C Lyden, Yogendra Kanthi, Mariana J Kaplan, Jason S Knight, David A Fox","doi":"10.1172/jci.insight.184975","DOIUrl":"https://doi.org/10.1172/jci.insight.184975","url":null,"abstract":"<p><p>The soluble variant of the ectopeptidase CD13 (sCD13), released from the cell surface by matrix metalloproteinase 14 (MMP14), is a potent pro-inflammatory mediator, displaying chemotactic, angiogenic, and arthritogenic properties through bradykinin receptor B1 (B1R). We reveal a link between sCD13 and amplified neutrophil-mediated inflammatory responses in SARS-CoV-2 infection. sCD13 was markedly elevated in COVID-19 patients and correlated with disease severity, variants, ethnicity, inflammation markers, and NETosis. Neutrophils treated with sCD13 showed heightened NETosis and chemotaxis which were inhibited by sCD13 receptor blockade. Meanwhile sCD13 did not induce platelet aggregation. Single-cell analysis of COVID-19 lungs revealed co-expression of CD13 and MMP14 by various cell types, and higher CD13 expression compared to controls. Neutrophils with high CD13 mRNA were enriched for genes associated with immaturity, though CD13 protein expression was lower. Histological examination of COVID-19 lungs revealed CD13-positive leukocytes trapped in vessels with fibrin thrombi. Flow cytometry confirmed the presence of B1R and a second sCD13 receptor, protease-activated receptor 4, on monocytes and neutrophils. These findings identify sCD13 as a potential instigator of COVID-19-associated NETosis, potentiating vascular stress and thromboembolic complications. The potent pro-inflammatory effects of sCD13 may contribute to severe COVID-19, suggesting that sCD13 and its receptors might be therapeutic targets.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763877","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}

{"title":"SEC24C deficiency causes trafficking and glycosylation abnormalities in an epileptic encephalopathy with cataracts and dyserythropoeisis.","authors":"Nina Bögershausen, Büsranur Cavdarli, Taylor Nagai, Miroslav P Milev, Alexander Wolff, Mahsa Mehranfar, Julia Schmidt, Dharmendra Choudhary, Óscar Gutiérrez-Gutiérrez, Lukas Cyganek, Djenann Saint-Dic, Arne Zibat, Karl Köhrer, Tassilo E Wollenweber, Dagmar Wieczorek, Janine Altmüller, Tatiana Borodina, Dilek Kaçar, Göknur Haliloğlu, Yun Li, Christian Thiel, Michael Sacher, Ela W Knapik, Gökhan Yigit, Bernd Wollnik","doi":"10.1172/jci.insight.173484","DOIUrl":"https://doi.org/10.1172/jci.insight.173484","url":null,"abstract":"<p><p>As a major component of intracellular trafficking, the coat protein complex II (COPII) is indispensable for cellular function during embryonic development and throughout life. The four SEC24 proteins (A-D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently only known for SEC24D. Here, we report that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with four affected individuals. We show that knockout of sec24C in zebrafish recapitulates important aspects of the human phenotype. SEC24C-deficient fibroblasts display alterations in the expression of several COPII components as well as impaired anterograde trafficking to the Golgi, indicating a severe impact on COPII function. Transcriptome analysis revealed that SEC24C deficiency also impacts the proteasome and autophagy pathways. Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggest a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709806","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}

{"title":"Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age.","authors":"Paula M Fraczek, Pamela Duran, Benjamin A Yang, Valeria Ferre, Leanne Alawieh, Jesus A Castor-Macias, Vivian T Wong, Steve D Guzman, Celeste Piotto, Klimentini Itsani, Jacqueline A Larouche, Carlos A Aguilar","doi":"10.1172/jci.insight.183706","DOIUrl":"https://doi.org/10.1172/jci.insight.183706","url":null,"abstract":"<p><p>Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709807","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}

{"title":"IFN-γand donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation .","authors":"Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Erika M Moore, Scott Furlan, Warren D Shlomchik","doi":"10.1172/jci.insight.190655","DOIUrl":"https://doi.org/10.1172/jci.insight.190655","url":null,"abstract":"<p><strong>Background: </strong>The graft-vs-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-γ is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-γ combined with donor leukocyte infusions (DLI) in myeloblastic malignancies that relapsed post-HLA-matched alloSCT.</p><p><strong>Methods: </strong>Patients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-γ for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-γ for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNAseq) to assess in vivo responses to IFN-γ by malignant myeloblasts.</p><p><strong>Results: </strong>IFN-γ monotherapy was well tolerated by all subjects (n=7). Treatment-related toxicities after DLI included: grade I-II graft-versus-host disease (n=5), immune effector cell-associated neurotoxicity syndrome (n=2), and idiopathic pulmonary syndrome (n=1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. ScRNAseq confirmed in vivo activation of IFN-γ response pathway in hematopoietic stem cell-like or myeloid progenitor cells after IFN-γ in analyzed samples.</p><p><strong>Conclusions: </strong>IFN-γ was safe and well tolerated in this phase I study of IFN-γ for relapsed AML/MDS post-alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach.TRIAL RESGISTRATION.</p><p><strong>Clinicaltrials: </strong>gov NCT04628338.</p><p><strong>Funding: </strong>The research was supported by The UPMC Hillman Cancer Center Cancer Immunology and Immunotherapy Program (CIIP) Pilot Award and Cure Within Reach: Drug Repurposing Clinical Trials to Impact Blood Cancers. Recombinant IFN-gamma (Actimmune®) was donated by Horizon Therapeutics.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709805","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}

{"title":"CFTR negatively reprograms Th2 cell responses and CFTR potentiation restrains allergic airway inflammation.","authors":"Mark Rusznak, Christopher M Thomas, Jian Zhang, Shinji Toki, Weisong Zhou, Masako Abney, Danielle M Yanda, Allison E Norlander, Craig A Hodges, Dawn C Newcomb, Mark H Kaplan, R Stokes Peebles, Daniel P Cook","doi":"10.1172/jci.insight.191098","DOIUrl":"10.1172/jci.insight.191098","url":null,"abstract":"<p><p>Type 2 inflammatory diseases are common in cystic fibrosis (CF) including asthma, sinusitis, and allergic bronchopulmonary aspergillosis. CD4+ T helper 2 (Th2) cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the cystic fibrosis transmembrane conductance regulator (CFTR), the mutated protein in CF, has a direct effect on Th2 development is unknown. Using murine models of CFTR deficiency and human CD4+ T cells, we show CD4+ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared to control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared to control mice. Culture of CFTR-deficient Th2 cells demonstrated increased IL-4Rα expression and increased sensitivity to IL-4 with greater induction of GATA3 and IL-13 compared to control Th2 cell cultures. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine secretion in bronchoalveolar lavage of \"humanized\" CFTR mice following Alternaria alternata extract challenge and decreased Th2 development in human T cell culture. Together, these data support a direct role of CFTR in regulating T cell sensitivity to IL-4 and demonstrate a potential CFTR-specific therapeutic strategy for Th2 cell-mediated allergic disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709804","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}

{"title":"Reduced high-density lipoprotein antioxidant function in patients with coronary artery disease and acute coronary syndrome.","authors":"Benjamin Sasko, Linda Scharow, Rhea Mueller, Monique Jaensch, Werner Dammermann, Felix S Seibert, Philipp Hillmeister, Ivo Buschmann, Martin Christ, Oliver Ritter, Nazha Hamdani, Christian Ukena, Timm H Westhoff, Theodoros Kelesidis, Nikolaos Pagonas","doi":"10.1172/jci.insight.187889","DOIUrl":"10.1172/jci.insight.187889","url":null,"abstract":"<p><strong>Results: </strong>Participants with CAD (n = 723) had 12% higher mean relative levels of nHDLox compared with those with invasively excluded CAD (n = 502, P < 0.001). Patients presenting with symptoms of an ACS had the highest nHDLox values when compared with the elective cohort (median 1.35, IQR 0.97 to 1.85, P < 0.001). In multivariate analysis adjusted for age, sex, body mass index, and hypertension, nHDLox was a strong independent predictor of ACS (P < 0.001) but not of CAD (P > 0.05).</p><p><strong>Conclusion: </strong>HDL antioxidant function is reduced in patients with CAD. nHDLox is strongly associated with ACS.</p><p><strong>Trial registration: </strong>German Clinical Trials Register DRKS00014037.</p><p><strong>Funding: </strong>Brandenburg Medical School Theodor Fontane, the BIOX Stiftung, and NIH grants R01AG059501 and R03AG059462.</p><p><strong>Background: </strong>High-density lipoprotein (HDL) function rather than its concentration plays an important role in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to determine whether reduced antioxidant function of HDL is associated with the presence of a stable CAD or acute coronary syndrome (ACS).</p><p><strong>Methods: </strong>HDL function was measured in 2 cohorts: 1225 patients admitted electively for coronary angiography and 196 patients with ACS. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function, as assessed by increased HDL-lipid peroxide content (HDLox), which was normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; unitless). Results are expressed as median with interquartile range (IQR).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692006","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":"Combination treatment with anti-RANKL and antibiotics for preventing joint destruction in septic arthritis.","authors":"Zhicheng Hu, Meghshree Deshmukh, Anders Jarneborn, Miriam Bollmann, Carmen Corciulo, Pradeep Kumar Kopparapu, Abukar Ali, Mattias N D Svensson, Cecilia Engdahl, Rille Pullerits, Majd Mohammad, Tao Jin","doi":"10.1172/jci.insight.184954","DOIUrl":"10.1172/jci.insight.184954","url":null,"abstract":"<p><p>Septic arthritis, the most severe joint disease, is frequently caused by Staphylococcus aureus (S. aureus). A substantial proportion of patients with septic arthritis experience poor joint outcomes, often necessitating joint replacement surgery. Here, we show that monocyte depletion confers full protection against bone erosion in a septic arthritis mouse model. In the infected synovium, Ly6Chi monocytes exhibited increased expression of osteoclastogenesis-related molecules, including CCR2, c-Fms, and RANK. S. aureus lipoproteins induced elevated levels of RANKL, MCSF, and CCL2 in joints, with synovial fibroblasts identified as the major RANKL producer. Anti-RANKL treatment prevented bone destruction in both local and hematogenous septic arthritis murine models. Importantly, combining anti-RANKL treatment with antibiotics provided robust protection against joint damage. Our results indicate that the infiltration and transformation of monocytes into bone-destructive, osteoclast-like cells are key mechanisms in septic arthritis. Combining anti-RANKL and antibiotic therapy represents a promising therapy against this devastating disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604850","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":"Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome.","authors":"Stephanie Waich, Karin Kreidl, Julia Vodopiutz, Arzu Meltem Demir, Adam R Pollio, Vojtěch Dostál, Kristian Pfaller, Marianna Parlato, Nadine Cerf-Bensussan, Rüdiger Adam, Georg F Vogel, Holm H Uhlig, Frank M Ruemmele, Thomas Müller, Michael W Hess, Andreas R Janecke, Lukas A Huber, Taras Valovka","doi":"10.1172/jci.insight.185508","DOIUrl":"10.1172/jci.insight.185508","url":null,"abstract":"<p><p>The osteo-oto-hepato-enteric (O2HE) syndrome is a severe autosomal recessive disease ascribed to loss-of-function mutations in the Unc-45 myosin chaperone A (UNC45A) gene. The clinical spectrum includes bone fragility, hearing loss, cholestasis, and life-threatening diarrhea associated with microvillus inclusion disease-like enteropathy. Here, we present molecular and functional analysis of the UNC45A c.710T>C (p.Leu237Pro) missense variant, which revealed a unique pathogenicity compared with other genetic variants causing UNC45A deficiency. The UNC45A p.Leu237Pro mutant retained chaperone activity, prevented myosin aggregation, and supported proper nonmuscle myosin II (NMII) filament formation in patient fibroblasts and human osteosarcoma (U2OS) cells. However, the mutant formed atypically stable oligomers and prevented chaperone-myosin complex dissociation, thereby inhibiting NMII functions. Similar to biallelic UNC45A deficiency, this resulted in impaired intracellular trafficking, defective recycling, and abnormal retention of transferrin at various endocytic sites. In particular, coexpression of wild-type protein attenuated the pathogenic effects of the variant by inhibiting excessive oligomer formation. Our results elucidate the pathogenic mechanisms and recessive characteristics of this variant and may aid in the development of targeted therapies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691940","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":"Macrophage-derived Fgl2 dampens antitumor immunity through regulation of FcγRIIB+CD8+ T cells in melanoma.","authors":"Kelsey B Bennion, Julia Miranda R Bazzano, Danya Liu, Maylene Wagener, Chrystal M Paulos, Mandy L Ford","doi":"10.1172/jci.insight.182563","DOIUrl":"10.1172/jci.insight.182563","url":null,"abstract":"<p><p>Cancer immunotherapy has emerged as a promising therapeutic modality but heterogeneity in patient responsiveness remains. Thus, greater understanding of the immunologic factors that dictate response to immunotherapy is critical to improve patient outcomes. Here, we show that fibrinogen-like protein 2 (Fgl2) is elevated in the setting of melanoma in humans and mice and plays a functional role in inhibiting the CD8+ T cell response. Surprisingly, the tumor itself is not the major cellular source of Fgl2. Instead, we found that macrophage-secreted Fgl2 dampens the CD8+ T cell response through binding and apoptosis of FcγRIIB+CD8+ T cells. This regulation was CD8+ T cell autonomous and not via an antigen-presenting cell intermediary, as absence of Fcgr2b from the CD8+ T cells rendered T cells insensitive to Fgl2 regulation. Fgl2 is robustly expressed by macrophages in 10 cancer types in humans and in 6 syngeneic tumor models in mice, underscoring the clinical relevance of Fgl2 as a therapeutic target to promote T cell activity and improve patient immunotherapeutic response.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691987","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}