JCI insightPub Date : 2025-07-15DOI: 10.1172/jci.insight.194882
Jessica N Maung, Yang Chen, Keegan S Hoose, Rose E Adler, Hadla Hariri, Mia J Dickson, Taryn A Hetrick, Gabriel A Ferguson, Rebecca L Schill, Hiroyuki Mori, Romina M Uranga, Kenneth T Lewis, Isabel D K Hermsmeyer, Donatella Gilio, Christopher de Solis, Amber Toliver, Noah Davidsohn, Elif A Oral, Ormond A MacDougald
{"title":"Effects of FGF21, soluble TGFBR2, and environmental temperature on metabolic dysfunction in lipodystrophic mice.","authors":"Jessica N Maung, Yang Chen, Keegan S Hoose, Rose E Adler, Hadla Hariri, Mia J Dickson, Taryn A Hetrick, Gabriel A Ferguson, Rebecca L Schill, Hiroyuki Mori, Romina M Uranga, Kenneth T Lewis, Isabel D K Hermsmeyer, Donatella Gilio, Christopher de Solis, Amber Toliver, Noah Davidsohn, Elif A Oral, Ormond A MacDougald","doi":"10.1172/jci.insight.194882","DOIUrl":"https://doi.org/10.1172/jci.insight.194882","url":null,"abstract":"<p><p>Metabolic health is influenced by adipose tissue, and obesity and lipodystrophy are characterized by inflammation and metabolic dysfunction. Whereas obesity and lipodystrophy treatments involve pharmacological approaches and lifestyle changes, these therapies require long-term, repeated dosing, and are not successful for all patients. Gene therapy with targets such as FGF21 and sTGFBR2 provides an alternative approach, specifically in lipodystrophy. Preclinical experiments in mice housed at 22°C are confounded by a mild cold stress not generally experienced by humans, which can negatively affect translation of metabolic therapeutics. In this study, we investigated effects of FGF21/sTGFBR2 combination gene therapy on obese and lipodystrophic mice, and how housing temperature influences therapeutic efficacy. In obese mice, FGF21/sTGFBR2 improved insulin resistance and hyperlipidemia more dramatically at warmer temperatures. In lipodystrophic mice on a high fat diet, combination therapy required adipose tissue to improve insulin resistance at 30°C, whereas FGF21 alone improved insulin resistance at 22°C. Transcriptomic analyses revealed that lipodystrophic mice had upregulated hepatic cell proliferation and fibrosis pathways, and that FGF21 promoted hepatic metabolism. Thus, metabolic dysfunction caused by lipodystrophy is improved by targeting FGF21 and TGFB signaling, but effectiveness in preclinical models may be dependent upon environmental temperature and presence of adipose tissue.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-15DOI: 10.1172/jci.insight.193091
Lisa A Ridnour, Robert Ys Cheng, William F Heinz, Milind Pore, Ana L Gonzalez, Elise L Femino, Rebecca L Moffat, Adelaide L Wink, Fatima Imtiaz, Leandro L Coutinho, Donna Butcher, Elijah F Edmondson, M Cristina Rangel, Stephen Tc Wong, Stanley Lipkowitz, Sharon A Glynn, Michael P Vitek, Daniel W McVicar, Xiaoxian Li, Stephen K Anderson, Nazareno Paolocci, Stephen M Hewitt, Stefan Ambs, Timothy R Billiar, Jenny C Chang, Stephen J Lockett, David A Wink
{"title":"Elevated tumor NOS2/COX2 promotes immunosuppressive phenotypes associated with poor survival in ER- breast cancer patients.","authors":"Lisa A Ridnour, Robert Ys Cheng, William F Heinz, Milind Pore, Ana L Gonzalez, Elise L Femino, Rebecca L Moffat, Adelaide L Wink, Fatima Imtiaz, Leandro L Coutinho, Donna Butcher, Elijah F Edmondson, M Cristina Rangel, Stephen Tc Wong, Stanley Lipkowitz, Sharon A Glynn, Michael P Vitek, Daniel W McVicar, Xiaoxian Li, Stephen K Anderson, Nazareno Paolocci, Stephen M Hewitt, Stefan Ambs, Timothy R Billiar, Jenny C Chang, Stephen J Lockett, David A Wink","doi":"10.1172/jci.insight.193091","DOIUrl":"https://doi.org/10.1172/jci.insight.193091","url":null,"abstract":"<p><p>Tumor immunosuppression impacts survival and treatment efficacy. Tumor NOS2/COX2 coexpression strongly predicts poor outcome in ER- breast cancer by promoting metastasis, drug resistance, cancer stemness, and immune suppression. Herein, a spatially distinct NOS2/COX2 and CD3+CD8+PD1- T effector (TEff) cell landscape correlated with poor survival in ER- tumors. NOS2 was primarily expressed at the tumor margin, whereas COX2 together with B7H4 was associated with immune desert regions lacking TEff cells, where a higher ratio of tumor NOS2 or COX2 to TEff cells predicted poor survival. Also, PDL1/PD1, regulatory T cells (TReg) and IDO1 were primarily associated with stroma restricted TEff cells. Regardless of the survival outcome, CD4+ T cells and macrophages were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to increased CD8+ TEff/CD4+ TReg ratio and CD8+ TEff infiltration while Nos2 deficiency had no significant effect, thus reinforcing our observations that COX2 is an essential component of immunosuppression through CD8+ TEff cell exclusion from the tumor. Our study indicates that tumor NOS2/COX2 expression plays a central role in tumor immune evasion, suggesting that strategies combining clinically available NOS2/COX2 inhibitors with immune therapy could provide effective options for the treatment of aggressive and drug-resistant ER- breast tumors.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-15DOI: 10.1172/jci.insight.192047
Kanglun Yu, Sagar Vyavahare, Dima W Alhamad, Husam Bensreti, Ling Ruan, Anik Tuladhar, Caihong Dai, Joseph C Shaver, Alok Tripathi, Kehong Ding, Rafal Pacholczyk, Marion A Cooley, Roger Zhong, Maribeth H Johnson, Jie Chen, Wendy B Bollag, Carlos M Isales, William D Hill, Mark W Hamrick, Sadanand Fulzele, Meghan E McGee-Lawrence
{"title":"Inhibition of AhR improves cortical bone and skeletal muscle function via preservation of neuromuscular junctions.","authors":"Kanglun Yu, Sagar Vyavahare, Dima W Alhamad, Husam Bensreti, Ling Ruan, Anik Tuladhar, Caihong Dai, Joseph C Shaver, Alok Tripathi, Kehong Ding, Rafal Pacholczyk, Marion A Cooley, Roger Zhong, Maribeth H Johnson, Jie Chen, Wendy B Bollag, Carlos M Isales, William D Hill, Mark W Hamrick, Sadanand Fulzele, Meghan E McGee-Lawrence","doi":"10.1172/jci.insight.192047","DOIUrl":"https://doi.org/10.1172/jci.insight.192047","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AhR) is proposed to mediate the frailty-promoting effects of the tryptophan metabolite kynurenine (Kyn), which increases with age in mice and humans. The goal of the current study was to test whether administration of pharmacological AhR inhibitors, BAY2416964 and CH-223191, could abrogate musculoskeletal decline in aging mice. Female C57BL/6 mice (18 months old) were treated with vehicle (VEH) or BAY2416964 (30 mg/kg) via daily oral gavage 5 days/week for 8 weeks. A second AhR antagonist, CH-223191, was administered to 16-month-old male and female C57BL/6 mice via intraperitoneal injections (3.3 mg/kg) 3 days/week for 12 weeks. While grip strength declined over time in VEH-treated mice, BAY2416964 preserved grip strength in part by improving integrity of neuromuscular junctions, an effect replicated during in vitro studies with siRNA against AhR. Cortical bone mass was also greater in BAY2416964- than VEH-treated mice. Similarly, CH-223191 treatment improved cortical bone and showed beneficial effects in skeletal muscle, including reducing oxidative stress as compared to VEH-treated animals. Transcriptomic and proteomic data from BAY2416964-treated mice supported a positive impact of BAY2416964 on molecular targets that affect neuromuscular junction function. Taken together, these data support AhR as a therapeutic target for improving musculoskeletal health during aging.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-15DOI: 10.1172/jci.insight.184435
Eric S Christenson, Brandon E Smith, Thanh J Nguyen, Alens Valentin, Soren Charmsaz, Nicole E Gross, Sarah M Shin, Alexei Hernandez, Won Jin Ho, Srinivasan Yegnasubramanian, James T Stivers
{"title":"Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity.","authors":"Eric S Christenson, Brandon E Smith, Thanh J Nguyen, Alens Valentin, Soren Charmsaz, Nicole E Gross, Sarah M Shin, Alexei Hernandez, Won Jin Ho, Srinivasan Yegnasubramanian, James T Stivers","doi":"10.1172/jci.insight.184435","DOIUrl":"https://doi.org/10.1172/jci.insight.184435","url":null,"abstract":"<p><p>Uracil DNA glycosylase (UNG) excises uracil and 5-fluorouracil bases from DNA and is implicated in fluorodeoxyuridine (FdU) resistance. Here we explore the effects of inhibiting UNG activity, or depleting the UNG protein, in two mouse syngeneic models for colorectal cancer. Overexpressing the uracil DNA glycosylase inhibitor protein in mismatch repair (MMR)-deficient MC38 cells injected into C57/B6 mice delayed tumor growth and prolonged survival when combined with FdU. Combining UNG inhibition with FdU numerically increased CD4+ T lymphocytes and B cells compared to FdU or UNG inhibition alone, suggesting an immune component to the effects. In contrast, shRNA depletion of UNG in the absence of FdU treatment resulted in 70% of mice clearing their tumors, and a 3-fold increase in overall survival compared to FdU. Analysis of MC38 tumor-infiltrating immune cells showed UNG depletion increased monocyte and dendritic cell populations, with CD8+ T cells also numerically increased. shRNA depletion of UNG in MMR-proficient CT-26 cells injected into Balb/C mice produced minimal benefit; the addition of anti-PD-1 antibody synergized with UNG-depletion to increase survival. Cytotoxic T cell depletion abolished the benefits of UNG depletion in both models. These findings suggest UNG inhibition and/or depletion could enhance antitumor immune response in humans.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-15DOI: 10.1172/jci.insight.188845
Sanjna Singh, Célia Fourrier, Kathryn J Hattersley, Leanne K Hein, Jemima Gore, Alexis Martin, Linh Vp Dang, Barbara King, Rachael A Protzman, Paul J Trim, Leonie K Heilbronn, Julien Bensalem, Timothy J Sargeant
{"title":"High protein does not change autophagy in human peripheral blood mononuclear cells after one hour.","authors":"Sanjna Singh, Célia Fourrier, Kathryn J Hattersley, Leanne K Hein, Jemima Gore, Alexis Martin, Linh Vp Dang, Barbara King, Rachael A Protzman, Paul J Trim, Leonie K Heilbronn, Julien Bensalem, Timothy J Sargeant","doi":"10.1172/jci.insight.188845","DOIUrl":"https://doi.org/10.1172/jci.insight.188845","url":null,"abstract":"<p><p>Autophagy is a catabolic quality control pathway that has been linked to neurodegenerative disease, atherosclerosis and ageing, and can be modified by nutrient availability in preclinical models. Consequently, there is immense public interest in stimulating autophagy in people. However, progress has been hampered by the lack of techniques to measure human autophagy. As a result, several key concepts in the field, including nutritional modulation of autophagy, have yet to be validated in humans. We conducted a single arm pre-post study in 42 healthy individuals, to assess whether an acute nutritional intervention could modify autophagy in humans. Two blood samples were collected per participant: after a 12 h overnight fast and 1 h post-consumption of a high protein meal. Autophagy turnover was assessed using a physiologically relevant measure of autophagic flux in peripheral blood mononuclear cells. A lysosomal inhibitor was added directly to whole blood, with the resulting build-up of autophagy marker LC3B-II designated as flux, and measured quantitatively via ELISA. Notably, consumption of a high protein meal had no impact on autophagy, with no differences between overnight fasting and postprandial autophagic flux. We observed sexual dimorphism in autophagy, with females having higher autophagic flux compared to males (p = 0.0031). Exploratory analyses revealed sex-specific correlations between autophagy, insulin and glucose signalling. Importantly, our findings show that an acute nutritional intervention (overnight fasting followed by consumption of a protein-rich meal) does not change autophagic flux in humans, highlighting the need to conduct further autophagy studies in humans.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-15DOI: 10.1172/jci.insight.191665
Lauren N Rust, Michael J Ricciardi, Savannah S Lutz, Sofiya Yusova, Johan J Louw, Aaron Yrizarry-Medina, Sreya Biswas, Miranda Fischer, Aaron Barber-Axthelm, Gavin Zilverberg, Lauren Bailey, Tonya Swanson, Rachael Tonelli, G W McElfresh, Brandon C Rosen, Thomas B Voigt, Christakis Panayiotou, Jack T Mauter, Noor Ghosh, Jenna Meanor, Giovana Godoy, Michael Axthelm, Jeremy Smedley, Mark K Slifka, Esper G Kallas, Gabriela Webb, Robert Zweig, Caralyn S Labriola, Benjamin N Bimber, Jonah B Sacha, David I Watkins, Benjamin J Burwitz
{"title":"Prophylactic and therapeutic neutralizing monoclonal antibody treatment prevents lethal yellow fever infection.","authors":"Lauren N Rust, Michael J Ricciardi, Savannah S Lutz, Sofiya Yusova, Johan J Louw, Aaron Yrizarry-Medina, Sreya Biswas, Miranda Fischer, Aaron Barber-Axthelm, Gavin Zilverberg, Lauren Bailey, Tonya Swanson, Rachael Tonelli, G W McElfresh, Brandon C Rosen, Thomas B Voigt, Christakis Panayiotou, Jack T Mauter, Noor Ghosh, Jenna Meanor, Giovana Godoy, Michael Axthelm, Jeremy Smedley, Mark K Slifka, Esper G Kallas, Gabriela Webb, Robert Zweig, Caralyn S Labriola, Benjamin N Bimber, Jonah B Sacha, David I Watkins, Benjamin J Burwitz","doi":"10.1172/jci.insight.191665","DOIUrl":"https://doi.org/10.1172/jci.insight.191665","url":null,"abstract":"<p><p>Yellow Fever virus (YFV) infection is fatal in 5-10% of the 200,000 yearly cases. There is currently no available antiviral treatment. We showed previously that administration of 50 mg/kg of a YFV-specific neutralizing monoclonal antibody (nmAb) at 2 days post-infection (dpi), prior to the onset of severe disease, protected YFV-infected rhesus macaques from death. To further explore the clinical applicability of our nmAb MBL-YFV-01, we treated rhesus macaques with a lower dose (10 mg/kg) of this nmAb prophylactically or therapeutically at 3.5 dpi. We show that a single prophylactic or therapeutic intravenous dose of our nmAb protects rhesus macaques from death following challenge. A comprehensive analysis of 167 inflammatory cytokine and chemokines revealed that protection was associated with significantly reduced expression of 125 of these markers, including type I interferons, IL6, and CCL2. This study further expands the potential clinical use of our YFV-specific nmAb, which could be used during an outbreak for immediate prophylactic immunity or for patients with measurable serum viremia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642567","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":"NSD1-916aa encoded by CircNSD1 contributes to AKI-to-CKD transition through inducing ferroptosis in tubular epithelial cells.","authors":"Li Gao, Junsheng Zhang, Chaoyi Chen, Sai Zhu, Xianglong Wei, Guiqin Tang, Sheng Wang, Yukai Wang, Xinran Liu, Ling Jiang, Yonggui Wu","doi":"10.1172/jci.insight.189130","DOIUrl":"https://doi.org/10.1172/jci.insight.189130","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is characterized by a rapid decline in renal function. In severe or recurrent cases, AKI can progress to chronic kidney disease (CKD), marked by renal inflammation and fibrosis. Despite the severity of these outcomes, early-stage diagnostic tools and pharmacological interventions for AKI-to-CKD progression remain limited. In this study, we examined circular RNA (circRNA) expression profiles in mouse renal cortex tissues 14 days post-ischemia/reperfusion (I/R) injury using circRNA sequencing. The renal biopsy samples of patients after AKI exhibited reduced CircNSD1 expression, which was inversely associated with inflammation and fibrosis. Overexpression of CircNSD1 attenuated ferroptosis in vivo and in vitro, while slowing AKI-to-CKD progression. Mechanistically, CircNSD1 downregulated ACSL4 and SlC39A14 expression through histone H3 lysine 36 (H3K36) methylation, a critical pathway regulating ferroptosis after AKI or hypoxia/reoxygenation (H/R) injury. Furthermore, we identified that CircNSD1 encoded a NSD1-916aa peptide, which may functionally contribute to its observed effect. Collectively, these findings demonstrated that CircNSD1 may serve as a diagnostic and therapeutic target for early detection of AKI-to-CKD transition.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.194075
Daria Golosova, Gaurav Kumar, Ko-Ting Lu, Patricia C Muskus Veitia, Ana Hantke Guixa, Kelsey K Wackman, Eva M Fekete, Daniel T Brozoski, Justin L Grobe, Maria Luisa S Sequeira-Lopez, R Ariel Gomez, Pablo Nakagawa, Curt D Sigmund
{"title":"Cullin-3 regulates the renal baroreceptor machinery that controls renin gene expression.","authors":"Daria Golosova, Gaurav Kumar, Ko-Ting Lu, Patricia C Muskus Veitia, Ana Hantke Guixa, Kelsey K Wackman, Eva M Fekete, Daniel T Brozoski, Justin L Grobe, Maria Luisa S Sequeira-Lopez, R Ariel Gomez, Pablo Nakagawa, Curt D Sigmund","doi":"10.1172/jci.insight.194075","DOIUrl":"https://doi.org/10.1172/jci.insight.194075","url":null,"abstract":"<p><p>Mutations in Cullin-3 (CUL3) cause hypertension (HTN). We examined the role of smooth muscle cell (SMC) CUL3 in the regulation of renin gene expression. Mice with SMC-specific CUL3 deletion (S-CUL3KO) developed severe HTN with paradoxically preserved levels of plasma angiotensin peptides and renal renin expression. Cre-recombinase was active in JG cells resulting in decreased CUL3 expression. We evaluated components of the renin cell baroreceptor and revealed preserved lamin A/C but decreased integrin β1 expression in S-CUL3KO. We hypothesized that Rab proteins are involved in integrin β1 downregulation. Silencing either Rab21 or Rab5 in CUL3-deficient HEK293 cells increased integrin β1 protein. Co-immunoprecipitation revealed a direct interaction between Rab5 and CUL3. CUL3-deficiency increased Rab5 suggesting it is regulated by a CUL3-mediated mechanism and that CUL3-deficiency results in loss of Rab protein turnover leading to enhanced integrin β1 internalization. We conclude that the loss of integrin β1 from juxtaglomerular cells impairs the mechanosensory function of the renin cell baroreceptor, which underlies the persistent renin expression observed in hypertensive S-CUL3KO mice. These findings provide insights into the molecular mechanisms of HTN, revealing that dysregulation of Rab proteins and integrin β1 in the kidney due to CUL3-deficiency contributes to the development of HTN.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.174235
Alexandra Christodoulou, Nutthakarn Suwankitwat, Jacob T Tietsort, Ryan Z Culbert, Julia Y Tsai, Fatima A Tarbal, Chengsong Zhu, Brian M Iritani
{"title":"Hem1 controls T cell activation, memory, and the regulated release of immunosuppressive and proinflammatory cytokines.","authors":"Alexandra Christodoulou, Nutthakarn Suwankitwat, Jacob T Tietsort, Ryan Z Culbert, Julia Y Tsai, Fatima A Tarbal, Chengsong Zhu, Brian M Iritani","doi":"10.1172/jci.insight.174235","DOIUrl":"https://doi.org/10.1172/jci.insight.174235","url":null,"abstract":"<p><p>Hematopoietic Protein-1 (Hem1) is a component of the WASP-family verprolin-homologous protein (WAVE) actin regulatory complex, which is activated downstream of multiple immune receptors. Mutations in the NCKAP1L gene encoding HEM1 have recently been found to result in severe Primary Immunodeficiency Disease (PID), characterized by recurrent respiratory infections, hyperinflammation, autoimmunity, and high mortality. However, how loss of Hem1 results in PID is unclear. To define the importance of Hem1 specifically in T cells, we generated constitutive and T cell specific Hem1 null mice. Hem1 deficient T cells exhibited an increased shift from naïve to memory T cells, and increased ratio of immunosuppressive regulatory to effector T cells. Loss of Hem1 resulted in hallmarks of T cell exhaustion including T cell lymphopenia, decreased activation and proliferation, increased expression of PD-1 and Tim3, and increased IL-10 production. In vitro TCR stimulation of CD4 T cells resulted in increased production of Th1 (IFN), Th2 (IL-5, IL-13), Th17 (IL-17, IL-22), and Treg (IL-10) cytokines. This correlated with reduced F-actin, increased expression of CD107a, and increased granzyme release indicative of increased granule membrane fusion and exocytosis. These results suggest that Hem-1 is critical for maintaining T cell activation, homeostasis and regulated cytokine production following antigen encounter.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-07-08DOI: 10.1172/jci.insight.194354
Riccardo Ronzoni, Ibrahim F Aldobyian, Elena Miranda, Narinder Heyer-Chauhan, Emma Lk Elliston, Juan Pérez, Annamaria Fra, James A Irving, David A Lomas
{"title":"Susceptibility of alpha1 antitrypsin deficiency variants to polymer blocking therapy.","authors":"Riccardo Ronzoni, Ibrahim F Aldobyian, Elena Miranda, Narinder Heyer-Chauhan, Emma Lk Elliston, Juan Pérez, Annamaria Fra, James A Irving, David A Lomas","doi":"10.1172/jci.insight.194354","DOIUrl":"https://doi.org/10.1172/jci.insight.194354","url":null,"abstract":"<p><p>The Z variant (Glu342Lys) causes alpha1 antitrypsin (AAT) to self-assemble into polymer chains that accumulate within hepatocytes causing liver disease and exposing a cryptic epitope recognised by the 2C1 monoclonal antibody (mAb). They can be blocked by the small molecule '716 that stabilises an intermediate on the polymerisation pathway. We have characterised 23 mutants of AAT in a cellular model to establish: (i) their ability to form intracellular polymers; (ii) whether polymer formation could be prevented by '716; and (iii) whether the polymers expose the 2C1 cryptic epitope. Most of the variants, including Mprocida (Leu41Pro), Mherleen (Pro369Leu), Mduarte (Asp256Val), Lfrankfurt (Pro255Thr), Yorzinuovi (Pro391His), Mwurzburg (Pro369Ser) and p.289S accumulated as intracellular polymers. Eleven formed polymers that were resistant to '716, including Mprocida, Mmalton (ΔPhe51), Lfrankfurt, Mduarte, S (Glu264Val), Mherleen, and Yorzinuovi. The '716 resistant mutants localise to a region of the AAT molecule separate from the binding site of the small molecule and form polymers that are less well-recognised by the 2C1 mAb. They are fully recognised by a novel 8A7 mAb that we developed to have a broader specificity. Our data suggest that individuals with these mutations are unlikely to benefit from treatment with '716 or its derivatives.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583958","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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