JCI insightPub Date : 2025-07-22DOI: 10.1172/jci.insight.191930
Kailin Yin, Lin Li, Xiaoyu Luo, Jason Neidleman, Arianna G Cassidy, Yarden Golan, Nida Ozarslan, Christine Y Lin, Unurzul Jigmeddagva, Mikias Ilala, Megan A Chidboy, Mary Prahl, Stephanie L Gaw, Nadia R Roan
{"title":"Pregnancy and lactation induce distinct immune responses to COVID-19 booster vaccination and SARS-CoV-2 breakthrough infection.","authors":"Kailin Yin, Lin Li, Xiaoyu Luo, Jason Neidleman, Arianna G Cassidy, Yarden Golan, Nida Ozarslan, Christine Y Lin, Unurzul Jigmeddagva, Mikias Ilala, Megan A Chidboy, Mary Prahl, Stephanie L Gaw, Nadia R Roan","doi":"10.1172/jci.insight.191930","DOIUrl":"10.1172/jci.insight.191930","url":null,"abstract":"<p><p>The widespread uptake of COVID-19 vaccines by women provided a unique opportunity to study the effects of pregnancy and lactation on immune responses to vaccination. Leveraging a cohort with well-defined SARS-CoV-2 exposure history, we found that the magnitude of humoral and cellular immune responses to vaccine-delivered SARS-CoV-2 spike was not affected by pregnancy or lactation status. However, vaccination during pregnancy elicited more stem-like SARS-CoV-2-specific CD4+ T cells. Moreover, breakthrough infection promoted spike-specific IgG in pregnant individuals in contrast with IgA in those lactating, suggesting that the pregnancy-to-lactation transition favors mucosal antibody responses. Breakthrough infection also reduced peripheral cytolytic SARS-CoV-2-specific CD8+ T cell frequencies during lactation but not pregnancy, which may reflect trafficking of the cells to mammary glands. Our study also uncovered an impact of pregnancy and lactation on global T cell phenotypes. In particular, lactating individuals preferentially exhibited a state of diminished T cell activation. Furthermore, breakthrough infection during pregnancy, but not lactation, diminished frequencies of activated CD8+ T cells, tissue-homing CD8+ T cells, and γδ T cells. Our findings support the notion that immunity during pregnancy and lactation adapts to benefit the fetus or breastfed infant, with implications for eliciting effective long-term immunity for these uniquely vulnerable groups.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 14","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690342","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 : 2025-07-22DOI: 10.1172/jci.insight.191245
Sara Monaci, Mengrui Wu, Hiroyuki Okada, Kedkanya Mesil, Byeong-Rak Keum, Maisa Monseff Rodrigues da Silva, Clifford J Rosen, Francesca Gori, Roland Baron
{"title":"PTH Counteracts Hippo Signaling via Src-dependent YAP Stabilization to Enhance Bone Marrow Stromal Cell Differentiation.","authors":"Sara Monaci, Mengrui Wu, Hiroyuki Okada, Kedkanya Mesil, Byeong-Rak Keum, Maisa Monseff Rodrigues da Silva, Clifford J Rosen, Francesca Gori, Roland Baron","doi":"10.1172/jci.insight.191245","DOIUrl":"https://doi.org/10.1172/jci.insight.191245","url":null,"abstract":"<p><p>Parathyroid hormone (PTH) regulates serum calcium and phosphate through its actions in bone and the kidney and is used to increase bone in osteoporosis treatment. In bone, PTH targets osteoblasts and osteocytes to regulate bone remodeling but also bone marrow stromal cells (BMSCs), regulating their differentiation in the osteoblast and/or the adipocyte lineages. PTH exerts its action through the PTH/PTH-related peptide (PTHrP) receptor (PTH1R), a G protein-coupled receptor (GPCR), activating adenylyl cyclase and phospholipase C (PLC). Although the effects of cAMP and PKA are well characterized, little is known about the effects of PLC activation or on the cross-talk between PTH signaling and other pathways. Here, bulk RNA-seq of PTH-treated murine BMSC line (W-20) revealed significant changes in the Hippo pathway. PTH stabilized YAP, a key target of Hippo, by decreasing YAP/LATS1 interaction, YAPS127 phosphorylation and YAP ubiquitination, leading to YAP nuclear translocation and expression of YAP target genes. Similar events occurred in osteocyte cell lines. This occurred via an increase in Src kinase activity: we identified YAPY428 as a key tyrosine residue phosphorylated by Src in response to PTH. Preventing YAP428 phosphorylation led to YAP instability, blocking both osteogenic and adipogenic differentiation of W-20 cells. These results demonstrate active crosstalk between the PTH/PTHrP and the Hippo signaling pathways and reveal that PTH signaling utilizes the PLC-Ca2+-Src tyrosine kinase signaling cascade to influence YAP stability, antagonizing Hippo signaling and favoring stromal cell differentiation. Thus, PTH signaling counteracts the effects of Hippo signaling in BMSCs to favor their differentiation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690335","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 : 2025-07-22DOI: 10.1172/jci.insight.188612
Justine Mathoux, Marc-Michel Wilson, Sujithra Srinivas, Gabrielle Litovskich, Leticia Villalba Benito, Cindy Tran, Jaideep Kesavan, Aileen Harnett, Theresa Auer, Amaya Sanz-Rodriguez, Mohammad Kh A E Alkhayyat, Mairéad Sullivan, Zining Liu, Yifan Huang, Austin Lacey, Norman Delanty, Jane Cryan, Francesca M Brett, Michael A Farrell, Donncha F O'Brien, Pablo M Casillas-Espinosa, Eva M Jimenez-Mateos, Jeffrey C Glennon, Mary Canavan, David C Henshall, Gary P Brennan
{"title":"N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy.","authors":"Justine Mathoux, Marc-Michel Wilson, Sujithra Srinivas, Gabrielle Litovskich, Leticia Villalba Benito, Cindy Tran, Jaideep Kesavan, Aileen Harnett, Theresa Auer, Amaya Sanz-Rodriguez, Mohammad Kh A E Alkhayyat, Mairéad Sullivan, Zining Liu, Yifan Huang, Austin Lacey, Norman Delanty, Jane Cryan, Francesca M Brett, Michael A Farrell, Donncha F O'Brien, Pablo M Casillas-Espinosa, Eva M Jimenez-Mateos, Jeffrey C Glennon, Mary Canavan, David C Henshall, Gary P Brennan","doi":"10.1172/jci.insight.188612","DOIUrl":"10.1172/jci.insight.188612","url":null,"abstract":"<p><p>Analogous to DNA methylation and protein phosphorylation, it is now well understood that RNA is also subject to extensive processing and modification. N6-methyladenosine (m6A) is the most abundant internal RNA modification and regulates RNA fate in several ways, including stability and translational efficiency. The role of m6A in both experimental and human epilepsy remains unknown. Here, we used transcriptome-wide m6A arrays to obtain a detailed analysis of the hippocampal m6A-ome from both mouse and human epilepsy samples. We combined this with human proteomic analyses and show that epileptic tissue displays disrupted metabolic and autophagic pathways that may be directly linked to m6A processing. Specifically, our results suggest that m6A levels inversely correlate with protein pathway activation. Finally, we show that elevated levels of m6A decrease seizure susceptibility and severity in mice. Together, our findings indicate that m6A represents an additional layer of gene regulation complexity in epilepsy and may contribute to the pathomechanisms that drive the development and maintenance of hyperexcitable brain networks.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 14","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690341","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 : 2025-07-22DOI: 10.1172/jci.insight.189858
Vera Kim, Takaya Misao, Hong Tian, Meggan Mackay, Cynthia Aranow, Sun Jung Kim
{"title":"Metabolic pathways within cTfh subsets and glucose-dependent activation of cTfh17 in SLE and healthy individuals.","authors":"Vera Kim, Takaya Misao, Hong Tian, Meggan Mackay, Cynthia Aranow, Sun Jung Kim","doi":"10.1172/jci.insight.189858","DOIUrl":"10.1172/jci.insight.189858","url":null,"abstract":"<p><p>Cellular metabolism plays a key role in T cell biology. Increased glycolysis and mitochondrial respiration have been identified in CD4+ helper T cells from both patients with systemic lupus erythematosus (SLE) and lupus mouse models. Inhibiting this metabolic activity can reduce T cell activation and ameliorate disease symptoms in lupus mice. However, the metabolic differences among circulating follicular helper T (cTfh) cell subsets in patients with SLE versus healthy controls (HCs) have not been thoroughly studied. While the frequencies of cTfh cells and their subsets were similar between patients with SLE and HCs, patients exhibited a higher proportion of activated ICOS+ programmed cell death 1-positive cells, which correlated with disease activity. cTfh17 cells from both patients with SLE and HCs demonstrated heightened glycolytic activity and expression of glycolysis-related genes compared with cTfh1 and cTfh2. Glucose deprivation significantly diminished costimulatory molecule expression and cytokine production, including IL-17A, IL-10, IL-2, and TNF-α. Glycolysis inhibition reduced the B cell activation capacity of cTfh17 cells. This glucose dependence was more pronounced in cTfh17 than cTfh2 from patients with SLE, but it similarly affected both cTfh2 and cTfh17 cells from HCs. These findings highlight distinct metabolic dependencies among cTfh subsets and the critical role of glycolysis in cTfh17-mediated B cell activation in SLE.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 14","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690340","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 : 2025-07-22DOI: 10.1172/jci.insight.193048
Ruoqi Chen, Lianqing Chen, Yu Tang, Xiaolin Shen, Yajie Wang, Peng Tang, Xingchao Shentu, Jie Sun
{"title":"Enhancing the potency of CAR-T cells against solid tumors through transcription factor engineering.","authors":"Ruoqi Chen, Lianqing Chen, Yu Tang, Xiaolin Shen, Yajie Wang, Peng Tang, Xingchao Shentu, Jie Sun","doi":"10.1172/jci.insight.193048","DOIUrl":"10.1172/jci.insight.193048","url":null,"abstract":"<p><p>Transcription factors (TFs) play a pivotal role in the development and differentiation of T cells. Recent studies have highlighted unique transcriptional profiles in chimeric antigen receptor T (CAR-T) cells derived from patients with favorable clinical outcomes, suggesting a potential link between TF modulation and improved therapeutic efficacy. Although CAR-T cell therapies have shown some success in treating hematological malignancies, they are limited by challenges such as poor persistence, functional exhaustion, and tumor resistance. To overcome these limitations, researchers have attempted to enhance the efficacy of CAR-T cells through manipulation of TF expression. This Review provides a comprehensive overview of TF engineering in CAR-T cells and elucidates the complex regulatory network between TFs. Notably, modification of basic leucine zipper ATF-like transcription factor in CAR-T cells results in contradictory functional outcomes in different studies. We summarize the potential factors leading to such results and elucidate the importance of setting up a relevant in vitro model to evaluate the effect of TFs on CAR-T cells. In conclusion, this Review highlights the latest advances in TF modifications and proposes strategies for harnessing these insights to empower CAR-T cells with superior antitumor efficacy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 14","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690338","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 : 2025-07-15DOI: 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.193787
Yizhe Sun, Janet Chou, Kevin D Dong, Steven P Gygi, Benjamin E Gewurz
{"title":"Insights into Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency.","authors":"Yizhe Sun, Janet Chou, Kevin D Dong, Steven P Gygi, Benjamin E Gewurz","doi":"10.1172/jci.insight.193787","DOIUrl":"10.1172/jci.insight.193787","url":null,"abstract":"<p><p>X-linked Lymphoproliferative Syndromes (XLP), arising from mutations in SH2D1A or XIAP genes, are characterized by fulminant Epstein-Barr Virus (EBV) infection. Lymphomas occur frequently in XLP-1 and in other congenital conditions with heightened EBV susceptibility, but not in XLP-2. Why XLP-2 patients are apparently protected from EBV-driven lymphomagenesis remains a key open question. To gain insights, newly EBV-infected versus receptor-stimulated primary B-cells from XLP-2 patients or with XIAP CRISPR editing were compared to healthy controls. XIAP perturbation impeded outgrowth of newly EBV-infected B-cells, but not that of CD40 ligand and interleukin-21 stimulated B-cells. XLP-2 deficient B-cells showed significantly lower EBV transformation efficiency than healthy controls. Interestingly, EBV-immortalized lymphoblastoid cell proliferation was not impaired by XIAP knockout, implicating an XIAP role in early EBV B-cell transformation. Mechanistically, nascent EBV infection activated p53-mediated apoptosis signaling, which was counteracted by XIAP in control cells. With XIAP deficiency, EBV markedly elevated apoptosis rates over the first two weeks of infection. Interferon-gamma, whose levels are increased with severe XLP2 EBV infection, markedly increased newly EBV-infected B-cell apoptosis. These findings underscored XIAP's crucial role in support of the earliest stages of EBV-mediated B-cell immortalization and provide insights into the curious absence of EBV+ lymphoma in XLP-2 patients.</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":"144659266","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.188459
Karin Lin, Nina Ly, Rejani B Kunjamma, Ngoc Vu, Bryan King, Holly M Robb, Eric G Mohler, Janani Sridar, Qi Hao, José Zavala-Solorio, Chunlian Zhang, Varahram Shahryari, Nick van Bruggen, Caitlin F Connelly, Bryson D Bennett, James J Lee, Carmela Sidrauski
{"title":"Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.","authors":"Karin Lin, Nina Ly, Rejani B Kunjamma, Ngoc Vu, Bryan King, Holly M Robb, Eric G Mohler, Janani Sridar, Qi Hao, José Zavala-Solorio, Chunlian Zhang, Varahram Shahryari, Nick van Bruggen, Caitlin F Connelly, Bryson D Bennett, James J Lee, Carmela Sidrauski","doi":"10.1172/jci.insight.188459","DOIUrl":"https://doi.org/10.1172/jci.insight.188459","url":null,"abstract":"<p><p>Maladaptive integrated stress response (ISR) activation is observed in human diseases of the brain. Genetic mutations of eIF2B, a critical mediator of protein synthesis, cause chronic pathway activation resulting in a leukodystrophy but the precise mechanism is unknown. We generated N208Y eIF2Bα mice and found that this metabolite binding mutation leads to destabilization of eIF2Bα, a systemic ISR, and neonatal lethality. 2BAct, an eIF2B activator, rescued lethality and significantly extended the lifespan of this severe model, underscoring its therapeutic potential in pediatric disease. Continuous treatment was required for survival, as withdrawal led to ISR induction in all tissues and rapid deterioration, thereby providing a model to assess the impact of the ISR in vivo by tuning drug availability. Single nuclei RNA-sequencing of the CNS identified astrocytes, oligodendrocytes, and ependymal cells as the cell types most susceptible to eIF2B dysfunction and revealed dysfunctional maturation of oligodendrocytes. Moreover, ISR activation decreased cholesterol biosynthesis, a process critical for myelin formation and maintenance. As such, persistent ISR engagement may contribute to pathology in other demyelinating diseases.</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":"144659265","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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