JCI insightPub Date : 2024-12-20DOI: 10.1172/jci.insight.185874
Dong Li, Suzanne Jan de Beur, Cuiping Hou, Maura Rz Ruzhnikov, Hilary Seeley, Garry R Cutting, Molly B Sheridan, Michael A Levine
{"title":"Recurrent small variants in NESP55/NESPAS associated with broad GNAS methylation defects and pseudohypoparathyroidism type 1B.","authors":"Dong Li, Suzanne Jan de Beur, Cuiping Hou, Maura Rz Ruzhnikov, Hilary Seeley, Garry R Cutting, Molly B Sheridan, Michael A Levine","doi":"10.1172/jci.insight.185874","DOIUrl":"10.1172/jci.insight.185874","url":null,"abstract":"<p><p>Pseudohypoparathyroidism type 1B (PHP1B) is associated with epigenetic changes in the maternal allele of the imprinted GNAS gene that inhibit expression of the α subunit of Gs (Gsα), thereby leading to parathyroid hormone resistance in renal proximal tubule cells where expression of Gsα from the paternal GNAS allele is normally silent. Although all patients with PHP1B show loss of methylation for the exon A/B differentially methylated region (DMR), some patients with autosomal dominant PHP1B (AD-PHP1B) and most patients with sporadic PHP1B have additional methylation defects that affect the DMRs corresponding to exons XL, AS1, and NESP. Because the genetic defect is unknown in most of these patients, we sought to identify the underlying genetic basis for AD-PHP1B in 2 multigenerational families with broad GNAS methylation defects and negative clinical exomes. Genome sequencing identified small GNAS variants in each family that were also present in unrelated individuals with PHP1B in a replication cohort. Maternal transmission of one GNAS microdeletion showed reduced penetrance in some unaffected patients. Expression of AS transcripts was increased, and NESP was decreased, in cells from affected patients. These results suggest that the small deletion activated AS transcription, leading to methylation of the NESP DMR with consequent inhibition of NESP transcription, and thereby provide a potential mechanism for PHP1B.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620661","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 : 2024-12-20DOI: 10.1172/jci.insight.182844
Andrew M Overmiller, Akihiko Uchiyama, Emma D Hope, Subhashree Nayak, Christopher G O'Neill, Kowser Hasneen, Yi-Wen Chen, Faiza Naz, Stefania Dell'Orso, Stephen R Brooks, Kan Jiang, Maria I Morasso
{"title":"Reprogramming of epidermal keratinocytes by PITX1 transforms the cutaneous cellular landscape and promotes wound healing.","authors":"Andrew M Overmiller, Akihiko Uchiyama, Emma D Hope, Subhashree Nayak, Christopher G O'Neill, Kowser Hasneen, Yi-Wen Chen, Faiza Naz, Stefania Dell'Orso, Stephen R Brooks, Kan Jiang, Maria I Morasso","doi":"10.1172/jci.insight.182844","DOIUrl":"10.1172/jci.insight.182844","url":null,"abstract":"<p><p>Cutaneous wound healing is a slow process that often terminates with permanent scarring while oral wounds, in contrast, regenerate after damage faster. Unique molecular networks in epidermal and oral epithelial keratinocytes contribute to the tissue-specific response to wounding, but key factors that establish those networks and how the keratinocytes interact with their cellular environment remain to be elucidated. The transcription factor PITX1 is highly expressed in the oral epithelium but is undetectable in cutaneous keratinocytes. To delineate if PITX1 contributes to oral keratinocyte identity, cell-cell interactions, and the improved wound healing capabilities, we ectopically expressed PITX1 in the epidermis of murine skin. Using comparative analysis of murine skin and oral (buccal) mucosa with single-cell RNA-Seq and spatial transcriptomics, we found that PITX1 expression enhances epidermal keratinocyte migration and proliferation and alters differentiation to a quasi-oral keratinocyte state. PITX1+ keratinocytes reprogrammed intercellular communication between skin-resident cells to mirror buccal tissue while stimulating the influx of neutrophils that establish a pro-inflammatory environment. Furthermore, PITX1+ skin healed significantly faster than control skin via increased keratinocyte activation and migration and a tunable inflammatory environment. These results illustrate that PITX1 programs oral keratinocyte identity and cellular interactions while revealing critical downstream networks that promote wound closure.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557859","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 : 2024-12-20DOI: 10.1172/jci.insight.178159
Zhiquan Liu, Siyu Chen, Chien-Hui Lo, Qing Wang, Yang Sun
{"title":"All-in-one AAV-mediated Nrl gene inactivation rescues retinal degeneration in Pde6a mice.","authors":"Zhiquan Liu, Siyu Chen, Chien-Hui Lo, Qing Wang, Yang Sun","doi":"10.1172/jci.insight.178159","DOIUrl":"10.1172/jci.insight.178159","url":null,"abstract":"<p><p>Retinitis pigmentosa (RP) is a complex group of inherited retinal diseases characterized by progressive death of photoreceptor cells and eventual blindness. Pde6a, which encodes a cGMP-specific phosphodiesterase, is a crucial pathogenic gene for autosomal recessive RP (RP43); there is no effective therapy for this form of RP. The compact CRISPR/Staphylococcus aureus Cas9 (CRISPR/SaCas9) system, which can be packaged into a single adeno-associated virus (AAV), holds promise for simplifying effective gene therapy. Here, we demonstrated that all-in-one AAV-SaCas9-mediated Nrl gene inactivation can efficiently prevent retinal degeneration in a RP mouse model with Pde6anmf363/nmf363 mutation. We screened single-guide RNAs capable of efficiently editing the mouse Nrl gene in N2a cells and then achieved effective gene editing by using a single AAV to codeliver SaCas9 and an optimal Nrl-sg2 into the mouse retina. Excitingly, in vivo inactivation of Nrl improved photoreceptor cell survival and rescued retinal function in treated Pde6a-deficient mice. Thus, we showed that a practical, gene-independent method, AAV-SaCas9-mediated Nrl inactivation, holds promise for future therapeutic applications in patients with RP.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583245","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 : 2024-12-20DOI: 10.1172/jci.insight.183889
Christopher Ag Booth, Juliette M Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A DeCaprio, Andrew A Lane
{"title":"BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid-dendritic cell leukemia.","authors":"Christopher Ag Booth, Juliette M Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A DeCaprio, Andrew A Lane","doi":"10.1172/jci.insight.183889","DOIUrl":"10.1172/jci.insight.183889","url":null,"abstract":"<p><p>MYB fusions are recurrently found in select cancers, including blastic plasmacytoid DC neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared with other blood cancers and, in some patients, are the only obvious somatic mutation detected. This suggests that they may alone be sufficient to drive DC transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but, mechanistically, how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that, in BPDCN leukemogenesis, MYB switches from being a regulator of DC lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in patients with BPDCN increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired DC differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583249","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 : 2024-12-20DOI: 10.1172/jci.insight.182064
Fernando Alvarez, Nicole V Acuff, Glenn M La Muraglia, Nazila Sabri, Marcos E Milla, Jill M Mooney, Matthew F Mackey, Mark Peakman, Ciriaco A Piccirillo
{"title":"The IL-2 SYNTHORIN molecule promotes functionally adapted Tregs in a preclinical model of type 1 diabetes.","authors":"Fernando Alvarez, Nicole V Acuff, Glenn M La Muraglia, Nazila Sabri, Marcos E Milla, Jill M Mooney, Matthew F Mackey, Mark Peakman, Ciriaco A Piccirillo","doi":"10.1172/jci.insight.182064","DOIUrl":"https://doi.org/10.1172/jci.insight.182064","url":null,"abstract":"<p><p>Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR'336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR'336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells' proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR'336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR'336 promoted the differentiation of IL-33-responsive (ST2+), IL-10-producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR'336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864008","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 : 2024-12-20DOI: 10.1172/jci.insight.183476
Eva Catenaccio, Jonathan Rochlin, Myles H Akabas, Lawrence F Brass, Harold K Simon
{"title":"The financial impact of MD-PhD training compared with MD training for academic physicians.","authors":"Eva Catenaccio, Jonathan Rochlin, Myles H Akabas, Lawrence F Brass, Harold K Simon","doi":"10.1172/jci.insight.183476","DOIUrl":"https://doi.org/10.1172/jci.insight.183476","url":null,"abstract":"<p><p>To reduce debt burden and encourage the pursuit of research-focused careers, most MD-PhD programs provide medical school tuition remission and an annual stipend. However, prolonged training compared with MD physicians postpones the time until MD-PhD physicians earn a full salary. We compared lifetime earning potential for MD-PhD physicians in academia with their MD colleagues in the same clinical specialty. We examined the relationship between earning potential based on specialty and the likelihood that MD-PhD physicians reported being engaged predominantly in research. Lifetime earning potential was estimated using 2020-2021 debt and compensation data for 77,701 academic physicians across 47 specialties. Self-reported research effort for 3,025 MD-PhD program alumni in academia was taken from the National MD-PhD Program Outcomes Study. We found that (a) MD-PhD physicians had a lower lifetime earning potential than MD physicians in the same specialty; (b) there was an inverse relationship between earning potential and research effort in different specialties, with MD-PhD physicians in high-earning specialties tending to spend less time on research; and (c) despite this, MD-PhD physicians in academia were more likely to choose clinical fields that allow more time for research.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864081","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 : 2024-12-20DOI: 10.1172/jci.insight.186078
Sydney I Ramirez, Paul G Lopez, Farhoud Faraji, Urvi M Parikh, Amy Heaps, Justin Ritz, Carlee Moser, Joseph J Eron, David Wohl, Judith Currier, Eric S Daar, Alex Greninger, Paul Klekotka, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Bjoern Peters, Michael D Hughes, Kara W Chew, Davey M Smith, Shane Crotty
{"title":"Early antiviral CD4+ and CD8+ T cells are associated with upper airway clearance of SARS-CoV-2.","authors":"Sydney I Ramirez, Paul G Lopez, Farhoud Faraji, Urvi M Parikh, Amy Heaps, Justin Ritz, Carlee Moser, Joseph J Eron, David Wohl, Judith Currier, Eric S Daar, Alex Greninger, Paul Klekotka, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Bjoern Peters, Michael D Hughes, Kara W Chew, Davey M Smith, Shane Crotty","doi":"10.1172/jci.insight.186078","DOIUrl":"https://doi.org/10.1172/jci.insight.186078","url":null,"abstract":"<p><p>T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, we assessed samples for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18-86 years old, approximately half of whom were considered at high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4+ and CD8+ T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4+ T cell and CD8+ T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4+ and CD8+ T cells during acute COVID-19.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864153","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 : 2024-12-20DOI: 10.1172/jci.insight.178820
Ivonne Melano, Tamiris Azamor, Camila Cs Caetano, Nikki M Meyer, Chineme Onwubueke, Anabelle Visperas, Débora Familiar-Macedo, Gielenny M Salem, Brandy-Lee Soos, Cassandra M Calabrese, Youn Jung Choi, Shuyang Chen, Younho Choi, Xianfang Wu, Zilton Vasconcelos, Suzy Aa Comhair, Karin Nielsen-Saines, Leonard H Calabrese, M Elaine Husni, Jae U Jung, Nicolas S Piuzzi, Suan-Sin Foo, Weiqiang Chen
{"title":"SARS-CoV-2 ORF8 drives osteoclastogenesis in preexisting immune-mediated inflammatory diseases.","authors":"Ivonne Melano, Tamiris Azamor, Camila Cs Caetano, Nikki M Meyer, Chineme Onwubueke, Anabelle Visperas, Débora Familiar-Macedo, Gielenny M Salem, Brandy-Lee Soos, Cassandra M Calabrese, Youn Jung Choi, Shuyang Chen, Younho Choi, Xianfang Wu, Zilton Vasconcelos, Suzy Aa Comhair, Karin Nielsen-Saines, Leonard H Calabrese, M Elaine Husni, Jae U Jung, Nicolas S Piuzzi, Suan-Sin Foo, Weiqiang Chen","doi":"10.1172/jci.insight.178820","DOIUrl":"https://doi.org/10.1172/jci.insight.178820","url":null,"abstract":"<p><p>Patients with immune-mediated inflammatory diseases (IMIDs) like rheumatoid arthritis (RA) are at higher risk for severe COVID-19 and long-term complications in bone health. Emerging clinical evidence demonstrated that SARS-CoV-2 infection reduces bone turnover and promotes bone loss, but the mechanism underlying worsened bone health remains elusive. This study sought to identify specific immune mediators that exacerbated preexisting IMIDs after SARS-CoV-2 exposure. Plasma samples from 4 groups were analyzed: healthy, IMID only, COVID-19 only, and COVID-19 + IMID. Using high-throughput multiplexed proteomics, we profiled 1,500 protein biomarkers and identified 148 unique biomarkers in COVID-19 patients with IMIDs, including elevated inflammatory cytokines (e.g., IL-17F) and bone resorption markers. Long-term circulating SARS-CoV-2 ORF8, a virulence factor for COVID-19, was detected in the COVID + IMID group. RA was one of the most common IMIDs in our study. ORF8 treatment of RA-derived human osteoblasts (RA-hOBs) increased levels of inflammatory (TNF, IL6, CCL2) and bone resorption (RANKL/osteoprotegerin ratio) markers compared with healthy controls. Supernatants from ORF8-treated RA-hOBs drove the differentiation of macrophages into osteoclast-like cells. These findings suggest that SARS-CoV-2 exposure can exacerbate IMIDs through ORF8-driven inflammation and osteoclastogenesis, highlighting potential therapeutic targets for managing COVID-19-induced bone pathologies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864156","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 : 2024-12-20DOI: 10.1172/jci.insight.185299
Titli Nargis, Charanya Muralidharan, Jacob R Enriquez, Jiayi E Wang, Kerim B Kaylan, Advaita Chakraborty, Sarida Pratuangtham, Kayla Figatner, Jennifer B Nelson, Sarah C May, Jerry L Nadler, Matthew B Boxer, David J Maloney, Sarah A Tersey, Raghavendra G Mirmira
{"title":"12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice.","authors":"Titli Nargis, Charanya Muralidharan, Jacob R Enriquez, Jiayi E Wang, Kerim B Kaylan, Advaita Chakraborty, Sarida Pratuangtham, Kayla Figatner, Jennifer B Nelson, Sarah C May, Jerry L Nadler, Matthew B Boxer, David J Maloney, Sarah A Tersey, Raghavendra G Mirmira","doi":"10.1172/jci.insight.185299","DOIUrl":"10.1172/jci.insight.185299","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages, with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift toward an immunosuppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in IFN response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620601","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 : 2024-12-20DOI: 10.1172/jci.insight.158127
Francesco Potì, Enrica Scalera, Renata Feuerborn, Josephine Fischer, Lilli Arndt, Georg Varga, Evangelia Pardali, Matthias D Seidl, Manfred Fobker, Gerhard Liebisch, Bettina Hesse, Alexander H Lukasz, Jan Rossaint, Beate E Kehrel, Frank Rosenbauer, Thomas Renné, Christina Christoffersen, Manuela Simoni, Ralph Burkhardt, Jerzy-Roch Nofer
{"title":"Sphingosine 1-phosphate receptor 1signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice.","authors":"Francesco Potì, Enrica Scalera, Renata Feuerborn, Josephine Fischer, Lilli Arndt, Georg Varga, Evangelia Pardali, Matthias D Seidl, Manfred Fobker, Gerhard Liebisch, Bettina Hesse, Alexander H Lukasz, Jan Rossaint, Beate E Kehrel, Frank Rosenbauer, Thomas Renné, Christina Christoffersen, Manuela Simoni, Ralph Burkhardt, Jerzy-Roch Nofer","doi":"10.1172/jci.insight.158127","DOIUrl":"10.1172/jci.insight.158127","url":null,"abstract":"<p><p>Sphingosine 1-phosphate (S1P) is a lysosphingolipid with antiatherogenic properties, but mechanisms underlying its effects remain unclear. We here investigated atherosclerosis development in cholesterol-rich diet-fed LDL receptor-deficient mice with high or low overexpression levels of S1P receptor 1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.1, interferon regulatory factor 8 (IRF8), and liver X receptor (LXR) and were skewed toward an M2-distinct phenotype characterized by enhanced production of IL-10, IL-1RA, and IL-5; increased ATP-binding cassette transporter A1- and G1-dependent cholesterol efflux; increased expression of MerTK and efferocytosis; and reduced apoptosis due to elevated B cell lymphoma 6 and Maf bZIP B. A similar macrophage phenotype was observed in mice administered S1P1-selective agonist KRP203. Mechanistically, the enhanced PU.1, IRF8, and LXR activity in S1P1-overexpressing macrophages led to downregulation of the cAMP-dependent PKA and activation of the signaling cascade encompassing protein kinases AKT and mTOR complex 1 as well as the late endosomal/lysosomal adaptor MAPK and mTOR activator 1. Atherosclerotic lesions in aortic roots and brachiocephalic arteries were profoundly or moderately reduced in mice with high and low S1P1 overexpression in macrophages, respectively. We conclude that S1P1 signaling polarizes macrophages toward an antiatherogenic functional phenotype and countervails the development of atherosclerosis in mice.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620665","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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