Science Translational Medicine最新文献

{"title":"Striatal stimulation enhances cognitive control and evidence processing in rodents and humans","authors":"Adriano E. Reimer,&nbsp;Evan M. Dastin-van Rijn,&nbsp;Jaejoong Kim,&nbsp;Megan E. Mensinger,&nbsp;Elizabeth M. Sachse,&nbsp;Aaron Wald,&nbsp;Eric Hoskins,&nbsp;Kartikeya Singh,&nbsp;Abigail Alpers,&nbsp;Dawson Cooper,&nbsp;Meng-Chen Lo,&nbsp;Amanda Ribeiro de Oliveira,&nbsp;Gregory Simandl,&nbsp;Nathaniel Stephenson,&nbsp;Alik S. Widge","doi":"10.1126/scitranslmed.adp1723","DOIUrl":"10.1126/scitranslmed.adp1723","url":null,"abstract":"<div >Brain disorders, in particular mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. Here, we propose a potential path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result using a set-shifting task in rats. DBS-like stimulation of the midstriatum improved reaction times without affecting accuracy, mirroring our human findings. Impulsivity, motivation, locomotor, and learning effects were ruled out through companion tasks and model-based analyses. To identify the specific cognitive processes affected, we applied reinforcement learning drift-diffusion modeling. This approach revealed that DBS-like stimulation enhanced evidence accumulation rates and lowered decision thresholds, improving domain-general cognitive control. Reanalysis of prior human data showed that the same mechanism applies in humans. This reverse/forward translational model could have near-term implications for clinical DBS practice and future trial design.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 778","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841784","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-γ–producing TH1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren’s disease","authors":"Yin-Hu Wang,&nbsp;Wenyi Li,&nbsp;Maxwell McDermott,&nbsp;Ga-Yeon Son,&nbsp;George Maiti,&nbsp;Fang Zhou,&nbsp;Anthony Y. Tao,&nbsp;Dimitrius Raphael,&nbsp;Andre L. Moreira,&nbsp;Boheng Shen,&nbsp;Martin Vaeth,&nbsp;Bettina Nadorp,&nbsp;Shukti Chakravarti,&nbsp;Rodrigo S. Lacruz,&nbsp;Stefan Feske","doi":"10.1126/scitranslmed.ado4856","DOIUrl":"10.1126/scitranslmed.ado4856","url":null,"abstract":"<div >Sjögren’s disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T_reg) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T_reg cells depend on store-operated Ca²⁺ entry (SOCE), which is mediated by ORAI1 Ca²⁺ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3⁺ T_reg cell–specific deletion of <i>Stim1</i> and <i>Stim2</i> develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (T_H1) and interferon (IFN) signaling. CD4⁺ T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ–dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4⁺ T cell–induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4⁺ T cells from patients with SjD, which indicate enhanced T_H1 but reduced memory T_reg cell function. Together, our study provides evidence for a critical role of dysfunctional T_reg cells and IFN-γ–producing T_H1 cells in the pathogenesis of SjD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 778","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841783","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":"The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron","authors":"Kyle W. Sloop,&nbsp;Amy L. Cox,&nbsp;David B. Wainscott,&nbsp;Alex White,&nbsp;Brian A. Droz,&nbsp;Cynthia Stutsman,&nbsp;Aaron D. Showalter,&nbsp;Todd M. Suter,&nbsp;James D. Dunbar,&nbsp;Brandy M. Snider,&nbsp;Libbey S. O’Farrell,&nbsp;Natalie Hewitt,&nbsp;J. Craig Ruble,&nbsp;Leah R. Padgett,&nbsp;Eric M. Woerly,&nbsp;Jeffrey A. Peterson,&nbsp;Tamer Coskun,&nbsp;Zhaomin Liu,&nbsp;David E. Coutant,&nbsp;Minrong Ai,&nbsp;Paul J. Emmerson,&nbsp;Panjamaporn Sangwung,&nbsp;Francis S. Willard","doi":"10.1126/scitranslmed.adp5765","DOIUrl":"10.1126/scitranslmed.adp5765","url":null,"abstract":"<div >Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [¹²⁵I]GLP-1(7-36)NH₂ or [³H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (<i>K</i>_i) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor <i>K</i>_i value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R (<i>Glp1r^S33W</i>) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in <i>Glp1r^S33W</i> rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 778","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841786","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":"Development of a fibrin-targeted theranostic for gastric cancer","authors":"Shadi A. Esfahani,&nbsp;Li Ma,&nbsp;Shriya Krishna,&nbsp;Hua Ma,&nbsp;Shvan J. Raheem,&nbsp;Sergey Shuvaev,&nbsp;Nicholas J. Rotile,&nbsp;Jonah Weigand-Whittier,&nbsp;Avery T. Boice,&nbsp;Nicholas Borges,&nbsp;Constantina A. Treaba,&nbsp;Caitlin Deffler,&nbsp;Himashinie Diyabalanage,&nbsp;Valerie Humblet,&nbsp;David E. Sosnovik,&nbsp;Umar Mahmood,&nbsp;Pedram Heidari,&nbsp;Angela Shih,&nbsp;Ciprian Catana,&nbsp;Matthew R. Strickland,&nbsp;Samuel J. Klempner,&nbsp;Peter Caravan","doi":"10.1126/scitranslmed.adn7218","DOIUrl":"10.1126/scitranslmed.adn7218","url":null,"abstract":"<div >Patients with advanced gastric cancer (GCa) have limited treatment options, and alternative treatment approaches are necessary to improve their clinical outcomes. Because fibrin is abundant in gastric tumors but not in healthy tissues, we hypothesized that fibrin could be used as a high-concentration depot for a high-energy beta-emitting cytotoxic radiopharmaceutical delivered to tumor cells. We showed that fibrin is present in 64 to 75% of primary gastric tumors and 50 to 100% of metastatic gastric adenocarcinoma cores. First-in-human ⁶⁴Cu-FBP8 fibrin–targeted positron emission tomography (PET) imaging in seven patients with gastric or gastroesophageal junction cancer showed high probe uptake in all target lesions with tumor-to-background (muscle) uptake ratios of 9.9 ± 6.6 in primary (<i>n</i> = 7) and 11.2 ± 6.6 in metastatic (<i>n</i> = 45) tumors. Using two mouse models of human GCa, one fibrin-high (SNU-16) and one fibrin-low (NCI-N87), we showed that PET imaging with a related fibrin-specific peptide, CM500, labeled with copper-64 (⁶⁴Cu-CM500) specifically bound to and precisely quantified tumor fibrin in both models. We then labeled the fibrin-specific peptide CM600 with yttrium-90 and showed that ⁹⁰Y-CM600 effectively decreased tumor growth in these mouse models. Mice carrying fibrin-high SNU-16 tumors experienced tumor growth inhibition and prolonged survival in response to either a single high dosage or fractionated lower dosage of ⁹⁰Y-CM600, whereas mice carrying fibrin-low NCI-N87 tumors experienced prolonged survival in response to a fractionated lower dosage of ⁹⁰Y-CM600. These results lay the foundation for a fibrin-targeted theranostic that may expand options for patients with advanced GCa.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 777","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809859","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":"ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools","authors":"Veronica D. Dahik,&nbsp;Pukar KC,&nbsp;Clément Materne,&nbsp;Canelle Reydellet,&nbsp;Marie Lhomme,&nbsp;Céline Cruciani-Guglielmacci,&nbsp;Jessica Denom,&nbsp;Eric Bun,&nbsp;Maharajah Ponnaiah,&nbsp;Florence Deknuydt,&nbsp;Eric Frisdal,&nbsp;Lise M. Hardy,&nbsp;Hervé Durand,&nbsp;Isabelle Guillas,&nbsp;Philippe Lesnik,&nbsp;Ivan Gudelj,&nbsp;Gordan Lauc,&nbsp;Maryse Guérin,&nbsp;Anatol Kontush,&nbsp;Antoine Soprani,&nbsp;Christophe Magnan,&nbsp;Marc Diedisheim,&nbsp;Olivier Bluteau,&nbsp;Nicolas Venteclef,&nbsp;Wilfried Le Goff","doi":"10.1126/scitranslmed.adi6682","DOIUrl":"10.1126/scitranslmed.adi6682","url":null,"abstract":"<div >The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between <i>ABCG1</i> expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 777","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809856","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":"Repurposing an epithelial sodium channel inhibitor as a therapy for murine and human skin inflammation","authors":"Mårten C. G. Winge,&nbsp;Mazen Nasrallah,&nbsp;Leandra V. Jackrazi,&nbsp;Konnie Q. Guo,&nbsp;Jessica M. Fuhriman,&nbsp;Rebecca Szafran,&nbsp;Muthukumar Ramanathan,&nbsp;Irina Gurevich,&nbsp;Ngon T. Nguyen,&nbsp;Zurab Siprashvili,&nbsp;Mohammed Inayathullah,&nbsp;Jayakumar Rajadas,&nbsp;Douglas F. Porter,&nbsp;Paul A. Khavari,&nbsp;Atul J. Butte,&nbsp;M. Peter Marinkovich","doi":"10.1126/scitranslmed.ade5915","DOIUrl":"10.1126/scitranslmed.ade5915","url":null,"abstract":"<div >Inflammatory skin disease is characterized by a pathologic interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is commonly used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify previously unidentified targets, we carried out a nonbiased informatics screen to identify drug compounds with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease, as a model, we used pharmacologic, transcriptomic, and proteomic characterization to find that benzamil, the benzyl derivative of the US Food and Drug Administration–approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Through three independent mouse models of skin inflammation (Rac1^G12V transgenic mice, topical imiquimod, and human skin xenografts from patients with psoriasis), we found that benzamil disrupted pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1. This reduced STAT3 and NF-κB signaling and downstream cytokine production in keratinocytes. Genetic knockdown of sodium channels or pharmacological inhibition by benzamil prevented excess Rac1-NCK1 binding and limited proinflammatory signaling pathway activation in patient-derived keratinocytes without systemic immunosuppression. Both systemic and topical applications of benzamil were efficacious, suggesting that it may be a potential therapeutic avenue for treating skin inflammation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 777","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809857","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":"ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes","authors":"Yann Grobs,&nbsp;Charlotte Romanet,&nbsp;Sarah-Eve Lemay,&nbsp;Alice Bourgeois,&nbsp;Pierre Voisine,&nbsp;Charlie Theberge,&nbsp;Melanie Sauvaget,&nbsp;Sandra Breuils-Bonnet,&nbsp;Sandra Martineau,&nbsp;Reem El Kabbout,&nbsp;Chanil Valasarajan,&nbsp;Prakash Chelladurai,&nbsp;Andreanne Pelletier,&nbsp;Manon Mougin,&nbsp;Elizabeth Dumais,&nbsp;Jean Perron,&nbsp;Nicolas Flamand,&nbsp;François Potus,&nbsp;Steeve Provencher,&nbsp;Soni Savai Pullamsetti,&nbsp;Olivier Boucherat,&nbsp;Sebastien Bonnet","doi":"10.1126/scitranslmed.ado7824","DOIUrl":"10.1126/scitranslmed.ado7824","url":null,"abstract":"<div >ATP citrate lyase (ACLY), a crucial enzyme in de novo lipid synthesis and histone acetylation, plays a key role in regulating vascular smooth muscle cell (VSMC) proliferation and survival. We found that human coronary and pulmonary artery tissues had up-regulated ACLY expression during vascular remodeling in coronary artery disease and pulmonary arterial hypertension. Pharmacological and genetic inhibition of ACLY in human primary cultured VSMCs isolated from the coronary arteries of patients with coronary artery diseases and from the distal pulmonary arteries of patients with pulmonary arterial hypertension resulted in reduced cellular proliferation and migration and increased susceptibility to apoptosis. These cellular changes were linked to diminished glycolysis, reduced lipid synthesis, impairment in general control nonrepressed protein 5 (GCN5)–dependent histone acetylation and suppression of the transcription factor FOXM1. In vivo studies using a pharmacological inhibitor and VSMC-specific <i>Acly</i> knockout mice showed that ACLY inhibition alleviated vascular remodeling. ACLY inhibition alleviated remodeling in carotid injury and ligation models in rodents and attenuated pulmonary arterial hypertension in Sugen/hypoxia rat and mouse models. Moreover, ACLY inhibition showed improvements in vascular remodeling in human ex vivo models, which included cultured human coronary artery and saphenous vein rings as well as precision-cut lung slices. Our results propose ACLY as a novel therapeutic target for treating complex vascular diseases, offering promising avenues for future clinical intervention.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 777","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809860","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":"Increased keratinocyte activity and PIEZO1 signaling contribute to paclitaxel-induced mechanical hypersensitivity","authors":"Alexander R. Mikesell,&nbsp;Elena Isaeva,&nbsp;Marie L. Schulte,&nbsp;Anthony D. Menzel,&nbsp;Anvitha Sriram,&nbsp;Megan M. Prahl,&nbsp;Seung Min Shin,&nbsp;Katelyn E. Sadler,&nbsp;Hongwei Yu,&nbsp;Cheryl L. Stucky","doi":"10.1126/scitranslmed.adn5629","DOIUrl":"10.1126/scitranslmed.adn5629","url":null,"abstract":"<div >Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether keratinocytes contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapy. We found that keratinocyte inhibition by either optogenetic or chemogenetic methods largely alleviated paclitaxel-induced mechanical hypersensitivity across acute and persistent time points from 2 days through 3 weeks. Furthermore, we found that paclitaxel exposure sensitized mouse and human keratinocytes to mechanical stimulation and enhanced currents of PIEZO1, a mechanosensitive channel highly expressed in keratinocytes. Deletion of PIEZO1 from keratinocytes alleviated paclitaxel-induced mechanical hypersensitivity in mice. These findings suggest that nonneuronal cutaneous cells contribute substantially to neuropathic pain and pave the way for the development of new pain relief strategies that target epidermal keratinocytes and PIEZO1.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 777","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809806","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":"Erratum for the Review “Engineering CAR-T therapies for autoimmune disease and beyond” by E. P. English et al.","authors":"","doi":"10.1126/scitranslmed.adu4655","DOIUrl":"10.1126/scitranslmed.adu4655","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 777","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812988","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":"Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation","authors":"Youran R. Zhang,&nbsp;Swapnil Keshari,&nbsp;Kazuo Kurihara,&nbsp;James Liu,&nbsp;Lindsay M. McKendrick,&nbsp;Chien-Sin Chen,&nbsp;Yufan Yang,&nbsp;Louis D. Falo Jr,&nbsp;Jishnu Das,&nbsp;Tina L. Sumpter,&nbsp;Daniel H. Kaplan","doi":"10.1126/scitranslmed.adq9133","DOIUrl":"10.1126/scitranslmed.adq9133","url":null,"abstract":"<div >Activation of dermal mast cells through the Mas-related G protein–coupled receptor B2 receptor (MrgprB2 in mice and MrgprX2 in humans) is a key component of numerous inflammatory skin diseases, including dermatitis and rosacea. Sensory neurons actively suppress mast cell activation through the regulated release of glutamate, resulting in reduced expression of <i>Mrgprb2</i> as well as genes associated with proteins found in mast cell granules. To determine whether exogenous glutamate receptor agonism could suppress mast cell function, we determined that mast cells have relatively selective expression of the glutamate receptor ionotropic, kainate 2 (GluK2). A GluK2-specific agonist, SYM2081, effectively inhibited mast cell degranulation in response to MrgprB2 agonism in both murine mast cells and human skin explants in vitro as well as in vivo after both intradermal and topical administration of SYM2081 to mice. Analyses of transcriptomic datasets from SYM2081-treated mast cells using standard differential expression approaches and an interpretable machine learning technique revealed a previously unrecognized cellular program coordinately regulated by GluK2 agonism. GluK2 agonism suppressed the expression of <i>Mrgprb2</i> and genes associated with mast cell proliferation. Suppression of mast cell proliferation by SYM2081 exposure was confirmed on the basis of reduced Ki-67 expression and BrdU incorporation in vitro and in vivo. Last, pretreatment with SYM2081 reduced skin inflammation in murine models of dermatitis and rosacea. Thus, agonism of GluK2 represents a promising approach to suppress mast cell activation and may prove beneficial as therapy for inflammatory diseases in which mast cell activation is pathogenic.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 777","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809861","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}