JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.182983
Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson
{"title":"ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology.","authors":"Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson","doi":"10.1172/jci.insight.182983","DOIUrl":"10.1172/jci.insight.182983","url":null,"abstract":"<p><p>Grover disease is an acquired epidermal blistering disorder in which keratinocytes lose intercellular connections. While its pathologic features are well defined, its etiology remains unclear, and there is no FDA-approved therapy. Interestingly, Grover disease was a common adverse event in clinical trials for cancer using B-RAF inhibitors, but it remained unknown how B-RAF blockade compromised skin integrity. Here, we identified ERK hyperactivation as a key driver of Grover disease pathology. We leveraged a fluorescent biosensor to confirm that the B-RAF inhibitors dabrafenib and vemurafenib paradoxically activated ERK in human keratinocytes and organotypic epidermis, disrupting cell-cell junctions and weakening epithelial integrity. Consistent with clinical data showing that concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed ERK and rescued cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in patient biopsies from vemurafenib-induced Grover disease and from spontaneous Grover disease, revealing a common etiology for both. Finally, in line with our recent identification of ERK hyperactivation in Darier disease, a genetic disorder with identical pathology to Grover disease, our studies uncovered that the pathogenic mechanisms of these diseases converge on ERK signaling and support MEK inhibition as a therapeutic strategy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346971","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 : 2024-11-08DOI: 10.1172/jci.insight.181329
Ariane R Pessentheiner, Nathanael J Spann, Chloe A Autran, Tae Gyu Oh, Kaare V Grunddal, Joanna Kc Coker, Chelsea D Painter, Bastian Ramms, Austin Wt Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno Pj de Winther, Hal M Hoffman, Martin Philpott, Adam P Cribbs, Udo Oppermann, Nathan E Lewis, Joseph L Witztum, Ruth Yu, Annette R Atkins, Michael Downes, Ron M Evans, Christopher K Glass, Lars Bode, Philip Lsm Gordts
{"title":"The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.","authors":"Ariane R Pessentheiner, Nathanael J Spann, Chloe A Autran, Tae Gyu Oh, Kaare V Grunddal, Joanna Kc Coker, Chelsea D Painter, Bastian Ramms, Austin Wt Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno Pj de Winther, Hal M Hoffman, Martin Philpott, Adam P Cribbs, Udo Oppermann, Nathan E Lewis, Joseph L Witztum, Ruth Yu, Annette R Atkins, Michael Downes, Ron M Evans, Christopher K Glass, Lars Bode, Philip Lsm Gordts","doi":"10.1172/jci.insight.181329","DOIUrl":"10.1172/jci.insight.181329","url":null,"abstract":"<p><p>Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of liver X receptor (LXR) and sterol regulatory element binding protein-1 (SREBP1). These acute antiinflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), IFN regulatory factor 2 (IRF2), B cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both s.c. and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346986","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 : 2024-11-08DOI: 10.1172/jci.insight.180584
Yongxing Wang, Vikram V Kulkarni, Jezreel PantaleónGarcía, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans
{"title":"The RNA receptor RIG-I binding synthetic oligodeoxynucleotide promotes pneumonia survival.","authors":"Yongxing Wang, Vikram V Kulkarni, Jezreel PantaleónGarcía, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans","doi":"10.1172/jci.insight.180584","DOIUrl":"10.1172/jci.insight.180584","url":null,"abstract":"<p><p>Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in TLR9, the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, and we discovered by mass spectroscopy that the RNA sensor RIG-I could also bind DNA-like ODN. ODN binding by RIG-I resulted in MAVS-dependent pneumonia-protective signaling events. While RIG-I is essential to native defenses against viral infections, we report that therapeutic RIG-I activation with ODN promoted pathogen killing and host survival following both viral and bacterial challenges. These data indicate that maximal ODN-induced pneumonia protection requires activation of both the TLR9/MyD88 and RIG-I/MAVS signaling pathways. These findings not only identify what we believe to be a novel pattern recognition receptor for DNA-like molecules, but reveal a potential therapeutic strategy to protect susceptible individuals against lethal pneumonias during periods of peak vulnerability.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365274","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 : 2024-11-08DOI: 10.1172/jci.insight.182664
Amy Y Sato, Meloney Cregor, Kevin McAndrews, Charles A Schurman, Eric Schaible, Jennifer Shutter, Punit Vyas, Bhawana Adhikari, Monte S Willis, Marjan Boerma, Tamara Alliston, Teresita Bellido
{"title":"Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease.","authors":"Amy Y Sato, Meloney Cregor, Kevin McAndrews, Charles A Schurman, Eric Schaible, Jennifer Shutter, Punit Vyas, Bhawana Adhikari, Monte S Willis, Marjan Boerma, Tamara Alliston, Teresita Bellido","doi":"10.1172/jci.insight.182664","DOIUrl":"10.1172/jci.insight.182664","url":null,"abstract":"<p><p>Despite their beneficial actions as immunosuppressants, glucocorticoids (GC) have devastating effects on the musculoskeletal and cardiac systems, as long-term treated patients exhibit high incidence of falls, bone fractures, and cardiovascular events. Herein, we show that GC upregulate simultaneously in bone, skeletal muscle, and the heart the expression of E3 ubiquitin ligases (atrogenes), known to stimulate the proteasomal degradation of proteins. Activation of vitamin D receptor (VDR) signaling with the VDR ligands calcitriol or eldecalcitol prevented GC-induced atrogene upregulation in vivo and ex vivo in bone/muscle organ cultures and preserved tissue structure/mass and function of the 3 tissues in vivo. Direct pharmacologic inhibition of the proteasome with carfilzomib also conferred musculoskeletal protection. Genetic loss of the atrogene MuRF1-mediated protein ubiquitination in ΔRING mice afforded temporary or sustained protection from GC excess in bone or skeletal and heart muscle. We concluded that the atrogene pathway downstream of MuRF1 underlies GC action in bone, muscle, and the heart, and it can be pharmacologically or genetically targeted to confer protection against the damaging actions of GC simultaneously in the 3 tissues.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465874","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 : 2024-11-08DOI: 10.1172/jci.insight.178644
Nune Markosyan, Il-Kyu Kim, Charu Arora, Liz Quinones-Ware, Nikhil Joshi, Noah Cheng, Emma Y Schechter, John W Tobias, Joseph E Hochberg, Emily Corse, Kang Liu, Varenka Rodriguez DiBlasi, Li-Chuan Eric Chan, Emer M Smyth, Garret A FitzGerald, Ben Z Stanger, Robert H Vonderheide
{"title":"Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing antitumor immunity.","authors":"Nune Markosyan, Il-Kyu Kim, Charu Arora, Liz Quinones-Ware, Nikhil Joshi, Noah Cheng, Emma Y Schechter, John W Tobias, Joseph E Hochberg, Emily Corse, Kang Liu, Varenka Rodriguez DiBlasi, Li-Chuan Eric Chan, Emer M Smyth, Garret A FitzGerald, Ben Z Stanger, Robert H Vonderheide","doi":"10.1172/jci.insight.178644","DOIUrl":"10.1172/jci.insight.178644","url":null,"abstract":"<p><p>Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME) by acting on the immune cells, but the impact of PGE2 signaling in tumor cells on the immunosuppressive TME is unclear. We demonstrate that deleting the PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME, activates T cells, and suppresses tumor growth. Knockout (KO) of Ptges (the gene encoding the PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D P53R172H Yfp CrePdx) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner. Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges- and Ptger4-KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α-induced killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4-KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected finding - a nonredundant role for the autocrine mPGES-1/PGE2/EP4 signaling axis in pancreatic cancer cells, further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing therapy in cancer.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287564","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 : 2024-11-08DOI: 10.1172/jci.insight.179126
Hannah Bd Duffy, Colleen Byrnes, Hongling Zhu, Galina Tuymetova, Y Terry Lee, Frances M Platt, Richard L Proia
{"title":"Deletion of Gba in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model.","authors":"Hannah Bd Duffy, Colleen Byrnes, Hongling Zhu, Galina Tuymetova, Y Terry Lee, Frances M Platt, Richard L Proia","doi":"10.1172/jci.insight.179126","DOIUrl":"10.1172/jci.insight.179126","url":null,"abstract":"<p><p>Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, which is responsible for encoding the enzyme glucocerebrosidase. Neuronopathic Gaucher disease is associated with microgliosis, astrogliosis, and neurodegeneration. However, the role that microglia, astrocytes, and neurons play in the disease remains to be determined. In the current study, we developed inducible, cell-type-specific Gba-KO mice to better understand the individual impacts of Gba deficiencies on microglia and neurons. Gba was conditionally knocked out either exclusively in microglia or neurons or throughout the body. These mouse models were developed using a tamoxifen-inducible Cre system, with tamoxifen administration commencing at weaning. Microglia-specific Gba-KO mice showed no signs of disease. However, the neuron-specific Gba KO resulted in a shortened lifespan, severe weight loss, and ataxia. These mice also had significant neurodegeneration, microgliosis, and astrogliosis accompanied by the accumulation of glucosylceramide and glucosylsphingosine, recapitulating Gaucher disease-like symptoms. These surprising findings reveal that, unlike the neuron-specific Gba deficiency, microglia-specific Gba deficiency alone does not induce disease. The neuronal Gaucher disease mouse model, with a median survival of 16 weeks, may be useful for future studies of pathogenesis and the evaluation of therapies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307753","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 : 2024-11-08DOI: 10.1172/jci.insight.182589
Benjamin I Burke, Ahmed Ismaeel, Douglas E Long, Lauren A Depa, Peyton T Coburn, Jensen Goh, Tolulope P Saliu, Bonnie J Walton, Ivan J Vechetti, Bailey D Peck, Taylor R Valentino, C Brooks Mobley, Hasiyet Memetimin, Dandan Wang, Brian S Finlin, Philip A Kern, Charlotte A Peterson, John J McCarthy, Yuan Wen
{"title":"Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise.","authors":"Benjamin I Burke, Ahmed Ismaeel, Douglas E Long, Lauren A Depa, Peyton T Coburn, Jensen Goh, Tolulope P Saliu, Bonnie J Walton, Ivan J Vechetti, Bailey D Peck, Taylor R Valentino, C Brooks Mobley, Hasiyet Memetimin, Dandan Wang, Brian S Finlin, Philip A Kern, Charlotte A Peterson, John J McCarthy, Yuan Wen","doi":"10.1172/jci.insight.182589","DOIUrl":"10.1172/jci.insight.182589","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) have emerged as important mediators of intertissue signaling and exercise adaptations. In this human study, we provide evidence that muscle-specific microRNA-1 (miR-1) was transferred to adipose tissue via EVs following an acute bout of resistance exercise. Using a multimodel machine learning automation tool, we discovered muscle primary miR-1 transcript and CD63+ EV count in circulation as top explanatory features for changes in adipose miR-1 levels in response to resistance exercise. RNA-Seq and in-silico prediction of miR-1 target genes identified caveolin 2 (CAV2) and tripartite motif containing 6 (TRIM6) as miR-1 target genes downregulated in the adipose tissue of a subset of participants with the highest increases in miR-1 levels following resistance exercise. Overexpression of miR-1 in differentiated human adipocyte-derived stem cells downregulated these miR-1 targets and enhanced catecholamine-induced lipolysis. These data identify a potential EV-mediated mechanism by which skeletal muscle communicates with adipose tissue and modulates lipolysis via miR-1.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346981","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 : 2024-11-08DOI: 10.1172/jci.insight.180081
Jennifer H Lawrence, Asha Patel, Melvin W King, Collin J Nadarajah, Richard Daneman, Erik S Musiek
{"title":"Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown.","authors":"Jennifer H Lawrence, Asha Patel, Melvin W King, Collin J Nadarajah, Richard Daneman, Erik S Musiek","doi":"10.1172/jci.insight.180081","DOIUrl":"10.1172/jci.insight.180081","url":null,"abstract":"<p><p>The blood-brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory dysfunction. While transporter-dependent efflux of some lipophilic substrates across the BBB shows circadian variation due to rhythmic transporter expression, basal transporter-independent permeability and leakage is nonrhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated LPS injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions; we then examined BBB permeability to a polar molecule that is not a transporter substrate, sodium fluorescein. We observed clear diurnal variation in inflammatory BBB permeability, with a striking increase in paracellular leak across the BBB specifically following evening LPS injection. Evening LPS led to persisting glia activation as well as inflammation in the brain that was not observed in the periphery. The exaggerated evening neuroinflammation and BBB disruption were suppressed by microglial depletion or through keeping mice in constant darkness. Our data show that diurnal rhythms in microglial inflammatory responses to LPS drive daily variability in BBB breakdown and reveal time of day as a key regulator of inflammatory BBB disruption.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 21","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604485","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 : 2024-11-08DOI: 10.1172/jci.insight.182876
Heike J Wobst, Andreu Viader, Giovanni Muncipinto, Ryan Hollibaugh, Daniel van Kalken, Christopher T Burkhart, Susan M Cantin, Rachel M Bates, Yannik Regimbald-Dumas, Liam Gross, Mitchell T Antalek, Joshua E Zweig, Frank Wu, T Justin Rettenmaier, Matthew T Labenski, Nicholas Pullen, Heather S Blanchette, Jaclyn L Henderson, Haoling H Weng, Toby A Vaughn, Dean G Brown, John P Throup, Joel C Barrish
{"title":"SLC6A19 inhibition facilitates urinary neutral amino acid excretion and lowers plasma phenylalanine.","authors":"Heike J Wobst, Andreu Viader, Giovanni Muncipinto, Ryan Hollibaugh, Daniel van Kalken, Christopher T Burkhart, Susan M Cantin, Rachel M Bates, Yannik Regimbald-Dumas, Liam Gross, Mitchell T Antalek, Joshua E Zweig, Frank Wu, T Justin Rettenmaier, Matthew T Labenski, Nicholas Pullen, Heather S Blanchette, Jaclyn L Henderson, Haoling H Weng, Toby A Vaughn, Dean G Brown, John P Throup, Joel C Barrish","doi":"10.1172/jci.insight.182876","DOIUrl":"10.1172/jci.insight.182876","url":null,"abstract":"<p><p>BACKGROUNDThe toxic accumulation of phenylalanine (Phe) in the brain underlies the neurological presentation of phenylketonuria (PKU). Solute carrier family 6 member 19 (SLC6A19) is the major transporter responsible for the (re)absorption of Phe in the kidney and intestine. Here, we describe the characterization of the first small molecule SLC6A19 inhibitor to enter clinical development for the treatment of PKU.METHODSC57Bl/6J WT and Pahenu2 mice were dosed with an inhibitor of SLC6A19 to investigate the effects on urinary amino acids and plasma Phe. In a phase 1 study, healthy human volunteers were dosed with JNT-517, an investigational oral inhibitor of SLC6A19. The primary objective of the study was safety. Secondary objectives included pharmacokinetic and pharmacodynamic studies.RESULTSInhibition of SLC6A19 increased the urinary excretion of Phe in a mouse model of PKU, thereby reducing plasma Phe levels. JNT-517, an investigational oral SLC6A19 inhibitor, was found to be safe and well tolerated and increased the urinary excretion of Phe in a phase 1 healthy volunteer study.CONCLUSIONSThese data indicate that pharmacological inhibition of SLC6A19 presents a promising approach to lower toxic elevated levels of amino acids found in PKU and related amino acid metabolism disorders by facilitating their renal elimination.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12622001222730.FUNDINGThe studies in this paper were funded by Jnana Therapeutics.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 21","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604503","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 : 2024-11-08DOI: 10.1172/jci.insight.164762
Chandra M Menendez, Jonathan Zuccolo, Susan E Swedo, Sean Reim, Brian Richmand, Hilla Ben-Pazi, Abraham Kovoor, Madeleine W Cunningham
{"title":"Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders.","authors":"Chandra M Menendez, Jonathan Zuccolo, Susan E Swedo, Sean Reim, Brian Richmand, Hilla Ben-Pazi, Abraham Kovoor, Madeleine W Cunningham","doi":"10.1172/jci.insight.164762","DOIUrl":"10.1172/jci.insight.164762","url":null,"abstract":"<p><p>Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea, and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine D2 receptor (D2R) signaling. However, AAb influence on dopamine D1 receptor (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia, a region of high dopamine receptor density. Here, we report a mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived monoclonal antibodies (mAbs), which induced both D1R G protein- and β-arrestin-transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346970","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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