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Go to The Journal of Clinical Investigation * About * Editors * Consulting Editors * For authors * Publication ethics * Publication alerts by email * Transfers * Advertising * Job board * Contact * Current issue * Past issues * By specialty * BACK * COVID-19 * Cardiology * Immunology * Metabolism * Nephrology * Oncology * Pulmonology * All ... * Videos * Collections * BACK * * Resource and Technical Advances * Clinical Medicine * Reviews * Editorials * Perspectives * JCI This Month * Top read articles * * JCI Insight * * Current issue * Past issues * Specialties * Collections * In-Press Preview * * * * * Editorials * Viewpoint * JCI This Month * Top read articles * Journal Details * About * Editors * Consulting Editors * For authors * Publication ethics * Publication alerts by email * Transfers * Advertising * Job board * Contact ISSUE PUBLISHED MARCH 8, 2024 * Volume 9, Issue 5 * Previous Issue GO TO SECTION: * Research Articles * Technical Advances * Physician-Scientist Development * Corrigendum * Editorial ENDOTHELIAL TDP-43 CONTROLS SPROUTING ANGIOGENESIS AND VASCULAR BARRIER INTEGRITY, AND ITS DELETION TRIGGERS NEUROINFLAMMATION Arribas et al. report roles for TDP-43 in the growth and stabilization of CNS vessels and identify endothelial TDP-43 as a factor potentially contributing to the vascular disorders and inflammation observed in patients diagnosed with TDP-43–associated diseases. The cover image shows blood–brain barrier disruption and neuroinflammation in a murine TDP-43iΔEC brain section stained for IB4 (green), the microglial marker Iba1 (light blue), and Ter119 (red blood cell marker; red). Technical Advances MODELING SKELETAL DYSPLASIA IN HURLER SYNDROME USING PATIENT-DERIVED BONE MARROW OSTEOPROGENITOR CELLS Samantha Donsante, … , Marta Serafini, Mara Riminucci Samantha Donsante, … , Marta Serafini, Mara Riminucci Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e173449. https://doi.org/10.1172/jci.insight.173449. View: Text | PDF MODELING SKELETAL DYSPLASIA IN HURLER SYNDROME USING PATIENT-DERIVED BONE MARROW OSTEOPROGENITOR CELLS * Text * PDF ABSTRACT Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet–based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders. AUTHORS Samantha Donsante, Alice Pievani, Biagio Palmisano, Melissa Finamore, Grazia Fazio, Alessandro Corsi, Andrea Biondi, Shunji Tomatsu, Rocco Piazza, Marta Serafini, Mara Riminucci × -------------------------------------------------------------------------------- ADAMTSL2 MUTATIONS DETERMINE THE PHENOTYPIC SEVERITY IN GELEOPHYSIC DYSPLASIA Vladimir Camarena, … , Katherina Walz, Mustafa Tekin Vladimir Camarena, … , Katherina Walz, Mustafa Tekin Published February 1, 2024 Citation Information: JCI Insight. 2024;9(5):e174417. https://doi.org/10.1172/jci.insight.174417. View: Text | PDF ADAMTSL2 MUTATIONS DETERMINE THE PHENOTYPIC SEVERITY IN GELEOPHYSIC DYSPLASIA * Text * PDF ABSTRACT Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but p.A165T exhibited a more severe impact. Mice carrying different allelic combinations revealed a spectrum of phenotypic severity, from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. Homozygous and hemizygous p.A165T mice survived but displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affected the expiration phase, and some of these animals had microscopic post-obstructive pneumonia. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction of the aortic root size. Histology verified the presence of hypertrophic cardiomyopathy with myocyte hypertrophy, chondroid metaplasia, and mild interstitial fibrosis. This study revealed a substantial correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1. AUTHORS Vladimir Camarena, Monique M. Williams, Alejo A. Morales, Mohammad F. Zafeer, Okan V. Kilic, Ali Kamiar, Clemer Abad, Monica A. Rasmussen, Laurence M. Briski, LéShon Peart, Guney Bademci, Deborah S. Barbouth, Sarah Smithson, Gaofeng Wang, Lina A. Shehadeh, Katherina Walz, Mustafa Tekin × -------------------------------------------------------------------------------- A MOUSE MODEL OF ZHU-TOKITA-TAKENOUCHI-KIM SYNDROME REVEALS INDISPENSABLE SON FUNCTIONS IN ORGAN DEVELOPMENT AND HEMATOPOIESIS Lana Vukadin, … , Ssang-Taek Steve Lim, Eun-Young Erin Ahn Lana Vukadin, … , Ssang-Taek Steve Lim, Eun-Young Erin Ahn Published January 30, 2024 Citation Information: JCI Insight. 2024;9(5):e175053. https://doi.org/10.1172/jci.insight.175053. View: Text | PDF A MOUSE MODEL OF ZHU-TOKITA-TAKENOUCHI-KIM SYNDROME REVEALS INDISPENSABLE SON FUNCTIONS IN ORGAN DEVELOPMENT AND HEMATOPOIESIS * Text * PDF ABSTRACT Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON. While patients with ZTTK syndrome live with numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/–) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/– mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/– mice, including leukopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency shifted cell fate more toward the myeloid lineage but compromised lymphoid lineage development by reducing genes required for lymphoid and B cell lineage specification. Additionally, Son haploinsufficiency caused inappropriate activation of erythroid genes and impaired erythropoiesis. These findings highlight the importance of the full gene expression of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction. AUTHORS Lana Vukadin, Bohye Park, Mostafa Mohamed, Huashi Li, Amr Elkholy, Alex Torrelli-Diljohn, Jung-Hyun Kim, Kyuho Jeong, James M. Murphy, Caitlin A. Harvey, Sophia Dunlap, Leah Gehrs, Hanna Lee, Hyung-Gyoon Kim, Jay Prakash Sah, Seth N. Lee, Denise Stanford, Robert A. Barrington, Jeremy B. Foote, Anna G. Sorace, Robert S. Welner, Blake E. Hildreth III, Ssang-Taek Steve Lim, Eun-Young Erin Ahn × Physician-Scientist Development INTERVENTIONS TO SUPPORT FELLOWSHIP APPLICATION SUCCESS AMONG PREDOCTORAL PHYSICIAN-SCIENTISTS Reiko Maki Fitzsimonds, … , Fred S. Gorelick, Barbara I. Kazmierczak Reiko Maki Fitzsimonds, … , Fred S. Gorelick, Barbara I. Kazmierczak Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e175857. https://doi.org/10.1172/jci.insight.175857. View: Text | PDF INTERVENTIONS TO SUPPORT FELLOWSHIP APPLICATION SUCCESS AMONG PREDOCTORAL PHYSICIAN-SCIENTISTS * Text * PDF ABSTRACT A critical element of physician-scientist training is the development and practice of core competencies that promote success in research careers. The ability to develop compelling training and research proposals is one such foundational skill. The NIH Ruth L. Kirschstein National Research Service Award (NRSA) individual fellowship for dual-degree students (F30, F31, or F31-Diversity) creates an ideal opportunity to provide formal instruction in grant-writing skills to physician-scientists early in training. In the guided process of preparing a predoctoral fellowship application, students learn to formulate clear short- and long-term research and training goals; construct a comprehensive, well-reasoned, and rigorous proposal; become familiar with funding agency priorities; and gain strategic insights into the peer review system. Beyond building scientific writing skills, the application process for an NRSA F30 or F31 is an opportunity for trainees to strengthen mentor-mentee relationships, identify learning opportunities key to their scientific development, and build effective research and mentoring teams. These skills also apply to developing future postdoctoral mentored K applications or faculty research program grants. Here, we outline key features of the structured proposal development training developed for students in the Yale MD-PhD Program and review outcomes associated with its implementation. AUTHORS Reiko Maki Fitzsimonds, Fred S. Gorelick, Barbara I. Kazmierczak × Editorial PHYSICIAN-SCIENTIST DEVELOPMENT: A NEW CATEGORY FOR SUPPORTING ALL STAGES OF THE PHYSICIAN-SCIENTIST PIPELINE Kathleen L. Collins Kathleen L. Collins Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e179940. https://doi.org/10.1172/jci.insight.179940. View: Text | PDF PHYSICIAN-SCIENTIST DEVELOPMENT: A NEW CATEGORY FOR SUPPORTING ALL STAGES OF THE PHYSICIAN-SCIENTIST PIPELINE * Text * PDF ABSTRACT AUTHORS Kathleen L. Collins × Research Articles A T CELL–BASED SARS-COV-2 SPIKE PROTEIN VACCINE PROVIDES PROTECTION WITHOUT ANTIBODIES Juan Shi, … , Liang Qiao, Lanying Du Juan Shi, … , Liang Qiao, Lanying Du Published January 23, 2024 Citation Information: JCI Insight. 2024;9(5):e155789. https://doi.org/10.1172/jci.insight.155789. View: Text | PDF A T CELL–BASED SARS-COV-2 SPIKE PROTEIN VACCINE PROVIDES PROTECTION WITHOUT ANTIBODIES * Text * PDF ABSTRACT SARS-CoV-2 spike–based vaccines are used to control the COVID-19 pandemic. However, emerging variants have become resistant to antibody neutralization and further mutations may lead to full resistance. We tested whether T cells alone could provide protection without antibodies. We designed a T cell–based vaccine in which SARS-CoV-2 spike sequences were rearranged and attached to ubiquitin. Immunization of mice with the vaccine induced no specific antibodies, but strong specific T cell responses. We challenged mice with SARS-CoV-2 wild-type strain or an Omicron variant after the immunization and monitored survival or viral titers in the lungs. The mice were significantly protected against death and weight loss caused by the SARS-CoV-2 wild-type strain, and the viral titers in the lungs of mice challenged with the SARS-CoV-2 wild-type strain or the Omicron variant were significantly reduced. Importantly, depletion of CD4+ or CD8+ T cells led to significant loss of the protection. Our analyses of spike protein sequences of the variants indicated that fewer than one-third presented by dominant HLA alleles were mutated and that most of the mutated epitopes were in the subunit 1 region. As the subunit 2 region is conservative, the vaccines targeting spike protein are expected to protect against future variants due to the T cell responses. AUTHORS Juan Shi, Jian Zheng, Xiujuan Zhang, Wanbo Tai, Ryan Compas, Jack Deno, Natalie Jachym, Abhishek K. Verma, Gang Wang, Xiaoqing Guan, Abby E. Odle, Yushun Wan, Fang Li, Stanley Perlman, Liang Qiao, Lanying Du × -------------------------------------------------------------------------------- HUMAN MAIT CELLS INHIBIT ALLOREACTIVE T CELL RESPONSES AND PROTECT AGAINST ACUTE GRAFT-VERSUS-HOST DISEASE Nana Talvard-Balland, … , Olivier Lantz, Sophie Caillat-Zucman Nana Talvard-Balland, … , Olivier Lantz, Sophie Caillat-Zucman Published February 1, 2024 Citation Information: JCI Insight. 2024;9(5):e166310. https://doi.org/10.1172/jci.insight.166310. View: Text | PDF HUMAN MAIT CELLS INHIBIT ALLOREACTIVE T CELL RESPONSES AND PROTECT AGAINST ACUTE GRAFT-VERSUS-HOST DISEASE * Text * PDF ABSTRACT Adoptive transfer of immunoregulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Mucosal-associated invariant T (MAIT) cells were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAIT cells in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic GVHD model. We found that MAIT cells, whether freshly purified or short-term expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAIT cells greatly delayed GVHD onset and decreased severity when transferred early after PBMC injection but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels and increased IL-10 levels. MAIT cells acted partly in a contact-dependent manner, which likely required direct interaction of their T cell receptor with MHC class I–related molecule (MR1) induced on host-reactive T cells. These results support the setup of clinical trials using MAIT cells as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders. AUTHORS Nana Talvard-Balland, Marion Lambert, Mathieu F. Chevalier, Norbert Minet, Marion Salou, Marie Tourret, Armelle Bohineust, Idan Milo, Véronique Parietti, Thomas Yvorra, Gérard Socié, Olivier Lantz, Sophie Caillat-Zucman × -------------------------------------------------------------------------------- AGE-RELATED DYSREGULATION OF INTESTINAL EPITHELIUM FUCOSYLATION IS LINKED TO AN INCREASED RISK OF COLON CANCER Zhihan Wang, … , Donald A. Jurivich, Ramkumar Mathur Zhihan Wang, … , Donald A. Jurivich, Ramkumar Mathur Published January 30, 2024 Citation Information: JCI Insight. 2024;9(5):e167676. https://doi.org/10.1172/jci.insight.167676. View: Text | PDF AGE-RELATED DYSREGULATION OF INTESTINAL EPITHELIUM FUCOSYLATION IS LINKED TO AN INCREASED RISK OF COLON CANCER * Text * PDF ABSTRACT Colon cancer affects people of all ages. However, its frequency, as well as the related morbidity and mortality, are high among older adults. The complex physiological changes in the aging gut substantially limit the development of cancer therapies. Here, we identify a potentially unique intestinal microenvironment that is linked with an increased risk of colon cancer in older adults. Our findings show that aging markedly influenced persistent fucosylation of the apical surfaces of intestinal epithelial cells, which resulted in a favorable environment for tumor growth. Furthermore, our findings shed light on the importance of the host-commensal interaction, which facilitates the dysregulation of fucosylation and promotes tumor growth as people get older. We analyzed colonic microbial populations at the species level to find changes associated with aging that could contribute to the development of colon cancer. Analysis of single-cell RNA-sequencing data from previous publications identified distinct epithelial cell subtypes involved in dysregulated fucosylation in older adults. Overall, our study provides compelling evidence that excessive fucosylation is associated with the development of colon cancer, that age-related changes increase vulnerability to colon cancer, and that a dysbiosis in microbial diversity and metabolic changes in the homeostasis of older mice dysregulate fucosylation levels with age. AUTHORS Zhihan Wang, Pan Gao, Kai Guo, Grace Schirrick, Jappreet Singh Gill, Jett Weis, Abby Lund Da Costa, Mansib Rahman, Het Mehta, Julia Fleecs, Shilpi Jain, Trishna Debnath, Junguk Hur, Nadeem Khan, Robert Sticca, Holly M. Brown-Borg, Donald A. Jurivich, Ramkumar Mathur × -------------------------------------------------------------------------------- NOREPINEPHRINE INDUCES ANOIKIS RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCER PRECURSOR CELLS Hunter D. Reavis, … , Laura M. Sanchez, Ronny Drapkin Hunter D. Reavis, … , Laura M. Sanchez, Ronny Drapkin Published January 25, 2024 Citation Information: JCI Insight. 2024;9(5):e170961. https://doi.org/10.1172/jci.insight.170961. View: Text | PDF NOREPINEPHRINE INDUCES ANOIKIS RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCER PRECURSOR CELLS * Text * PDF ABSTRACT High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a β-adrenergic receptor–dependent (β-AR–dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the β-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC. AUTHORS Hunter D. Reavis, Stefan M. Gysler, Grace B. McKenney, Matthew Knarr, Hannah J. Lusk, Priyanka Rawat, Hannah S. Rendulich, Marilyn A. Mitchell, Dara S. Berger, Jamie S. Moon, Suyeon Ryu, Monica Mainigi, Marcin P. Iwanicki, Dave S. Hoon, Laura M. Sanchez, Ronny Drapkin × -------------------------------------------------------------------------------- DDIT4L REGULATES MITOCHONDRIAL AND INNATE IMMUNE ACTIVITIES IN EARLY LIFE Christina Michalski, … , Ramon I. Klein Geltink, Pascal M. Lavoie Christina Michalski, … , Ramon I. Klein Geltink, Pascal M. Lavoie Published February 6, 2024 Citation Information: JCI Insight. 2024;9(5):e172312. https://doi.org/10.1172/jci.insight.172312. View: Text | PDF DDIT4L REGULATES MITOCHONDRIAL AND INNATE IMMUNE ACTIVITIES IN EARLY LIFE * Text * PDF ABSTRACT Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development. AUTHORS Christina Michalski, Claire Cheung, Ju Hee Oh, Emma Ackermann, Constantin R. Popescu, Anne-Sophie Archambault, Martin A. Prusinkiewicz, Rachel Da Silva, Abdelilah Majdoubi, Marina Viñeta Paramo, Rui Yang Xu, Frederic Reicherz, Annette E. Patterson, Liam Golding, Ashish A. Sharma, Chinten J. Lim, Paul C. Orban, Ramon I. Klein Geltink, Pascal M. Lavoie × -------------------------------------------------------------------------------- PREX1 IMPROVES HOMEOSTATIC PROLIFERATION TO MAINTAIN A NAIVE CD4+ T CELL COMPARTMENT IN OLDER AGE Huimin Zhang, … , Cornelia M. Weyand, Jӧrg J. Goronzy Huimin Zhang, … , Cornelia M. Weyand, Jӧrg J. Goronzy Published February 8, 2024 Citation Information: JCI Insight. 2024;9(5):e172848. https://doi.org/10.1172/jci.insight.172848. View: Text | PDF PREX1 IMPROVES HOMEOSTATIC PROLIFERATION TO MAINTAIN A NAIVE CD4+ T CELL COMPARTMENT IN OLDER AGE * Text * PDF ABSTRACT The human adult immune system maintains normal T cell counts and compensates for T cell loss throughout life, mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naive CD4+ T cell compartment into older age. Here, we describe that naive CD4+ T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 in older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naive cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation. AUTHORS Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R. Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M. Weyand, Jӧrg J. Goronzy × -------------------------------------------------------------------------------- TREGS FROM HUMAN BLOOD DIFFERENTIATE INTO NONLYMPHOID TISSUE–RESIDENT EFFECTOR CELLS UPON TNFR2 COSTIMULATION Mark Mensink, … , Sander de Kivit, Jannie Borst Mark Mensink, … , Sander de Kivit, Jannie Borst Published January 30, 2024 Citation Information: JCI Insight. 2024;9(5):e172942. https://doi.org/10.1172/jci.insight.172942. View: Text | PDF TREGS FROM HUMAN BLOOD DIFFERENTIATE INTO NONLYMPHOID TISSUE–RESIDENT EFFECTOR CELLS UPON TNFR2 COSTIMULATION * Text * PDF ABSTRACT Tregs can facilitate transplant tolerance and attenuate autoimmune and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg expansion and function in vivo and to create therapeutic Treg products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naive, thymus-derived Tregs (tTregs) from human blood that promotes their differentiation into nonlymphoid tissue–resident (NLT-resident) effector Tregs, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue–resident (LT-resident) Treg phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ tTregs and conventional T cells (Tconvs), followed by bioinformatic comparison with published transcriptomic Treg signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promoted tTreg capacity for survival, migration, immunosuppression, and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTregs. Flow cytometry validated the presence of the TNFR2-driven tTreg signature in effector/memory Tregs from the human placenta, as opposed to blood. Thus, TNFR2 can be exploited as a driver of NLT-resident tTreg differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease. AUTHORS Mark Mensink, Lotte J. Verleng, Ellen Schrama, George M.C. Janssen, Rayman T.N. Tjokrodirijo, Peter A. van Veelen, Qinyue Jiang, M. Fernanda Pascutti, Marie-Louise van der Hoorn, Michael Eikmans, Sander de Kivit, Jannie Borst × -------------------------------------------------------------------------------- MACROPHAGE-ENRICHED SECTM1A PROMOTES EFFICIENT EFFEROCYTOSIS TO ATTENUATE ISCHEMIA/REPERFUSION-INDUCED CARDIAC INJURY Xiaohong Wang, … , Wei Huang, Guo-Chang Fan Xiaohong Wang, … , Wei Huang, Guo-Chang Fan Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e173832. https://doi.org/10.1172/jci.insight.173832. View: Text | PDF MACROPHAGE-ENRICHED SECTM1A PROMOTES EFFICIENT EFFEROCYTOSIS TO ATTENUATE ISCHEMIA/REPERFUSION-INDUCED CARDIAC INJURY * Text * PDF ABSTRACT Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage–enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury. AUTHORS Xiaohong Wang, Wa Du, Yutian Li, Hui-Hui Yang, Yu Zhang, Rubab Akbar, Hannah Morgan, Tianqing Peng, Jing Chen, Sakthivel Sadayappan, Yueh-Chiang Hu, Yanbo Fan, Wei Huang, Guo-Chang Fan × -------------------------------------------------------------------------------- LOSS OF T FOLLICULAR REGULATORY CELL–DERIVED IL-1R2 AUGMENTS GERMINAL CENTER REACTIONS VIA INCREASED IL-1 Katerina Pyrillou, … , Ziad Mallat, Murray C.H. Clarke Katerina Pyrillou, … , Ziad Mallat, Murray C.H. Clarke Published February 8, 2024 Citation Information: JCI Insight. 2024;9(5):e174005. https://doi.org/10.1172/jci.insight.174005. View: Text | PDF LOSS OF T FOLLICULAR REGULATORY CELL–DERIVED IL-1R2 AUGMENTS GERMINAL CENTER REACTIONS VIA INCREASED IL-1 * Text * PDF ABSTRACT Inappropriate immune activity is key in the pathogenesis of multiple diseases, and it is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector owing to its powerful role in both innate and adaptive immunity, and, thus, it is tightly controlled at multiple levels. IL-1R2 antagonizes IL-1, but effects of losing this regulation are unknown. We found that IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal center (GC) T follicular regulatory (Tfr) cells increased the GC response after a first, but not booster, immunization, with an increase in T follicular helper (Tfh) cells, GC B cells, and antigen-specific antibodies, which was reversed upon IL-1 blockade. However, IL-1 signaling is not obligate for GC reactions, as WT and Il1r1–/– mice showed equivalent phenotypes, suggesting that GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2–/– mice did not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulated it, implying that compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn’s disease had lower serum IL-1R2. All together, we show that IL-1R2 controls important aspects of innate and adaptive immunity and that IL-1R2 level may contribute to human disease propensity and/or progression. AUTHORS Katerina Pyrillou, Melanie Humphry, Lauren A. Kitt, Amanda Rodgers, Meritxell Nus, Martin R. Bennett, Kenneth G.C. Smith, Paul A. Lyons, Ziad Mallat, Murray C.H. Clarke × -------------------------------------------------------------------------------- HIGH-MOBILITY GROUP BOX 1 INCREASES PLATELET SURFACE P2Y12 AND PLATELET ACTIVATION IN SICKLE CELL DISEASE Deirdre Nolfi-Donegan, … , Cheryl A. Hillery, Sruti Shiva Deirdre Nolfi-Donegan, … , Cheryl A. Hillery, Sruti Shiva Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e174575. https://doi.org/10.1172/jci.insight.174575. View: Text | PDF HIGH-MOBILITY GROUP BOX 1 INCREASES PLATELET SURFACE P2Y12 AND PLATELET ACTIVATION IN SICKLE CELL DISEASE * Text * PDF ABSTRACT Thrombosis and inflammation are intimately linked and synergistically contribute to the pathogenesis of numerous thromboinflammatory diseases, including sickle cell disease (SCD). While platelets are central to thrombogenesis and inflammation, the molecular mechanisms of crosstalk between the 2 remain elusive. High-mobility group box 1 (HMGB1) regulates inflammation and stimulates platelet activation through Toll-like receptor 4. However, it remains unclear whether HMGB1 modulates other thrombotic agonists to regulate platelet activation. Herein, using human platelets, we demonstrate that HMGB1 significantly enhanced ADP-mediated platelet activation. Furthermore, inhibition of the purinergic receptor P2Y12 attenuated HMGB1-dependent platelet activation. Mechanistically, we show that HMGB1 stimulated ADP secretion, while concomitantly increasing P2Y12 levels at the platelet membrane. We show that in SCD patients, increased plasma HMGB1 levels were associated with heightened platelet activation and surface P2Y12 expression. Treatment of healthy platelets with plasma from SCD patients enhanced platelet activation and surface P2Y12, and increased sensitivity to ADP-mediated activation, and these effects were linked to plasma HMGB1. We conclude that HMGB1-mediated platelet activation involves ADP-dependent P2Y12 signaling, and HMGB1 primes platelets for ADP signaling. This complementary agonism between ADP and HMGB1 furthers the understanding of thromboinflammatory signaling in conditions such as SCD, and provides insight for therapeutic P2Y12 inhibition. AUTHORS Deirdre Nolfi-Donegan, Gowtham K. Annarapu, Claudette St. Croix, Michael Calderon, Cheryl A. Hillery, Sruti Shiva × -------------------------------------------------------------------------------- ACTIVATOR PROTEIN TRANSCRIPTION FACTORS COORDINATE HUMAN IL-33 EXPRESSION FROM NONCANONICAL PROMOTERS IN CHRONIC AIRWAY DISEASE Heather E. Raphael, … , Bo Zhang, Jen Alexander-Brett Heather E. Raphael, … , Bo Zhang, Jen Alexander-Brett Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e174786. https://doi.org/10.1172/jci.insight.174786. View: Text | PDF ACTIVATOR PROTEIN TRANSCRIPTION FACTORS COORDINATE HUMAN IL-33 EXPRESSION FROM NONCANONICAL PROMOTERS IN CHRONIC AIRWAY DISEASE * Text * PDF ABSTRACT IL-33 is a cytokine central to type 2 immune pathology in chronic airway disease. This cytokine is abundantly expressed in the respiratory epithelium and increased in disease, but how expression is regulated is undefined. Here we show that increased IL33 expression occurs from multiple noncanonical promoters in human chronic obstructive pulmonary disease (COPD), and it facilitates production of alternatively spliced isoforms in airway cells. We found that phorbol 12-myristate 13-acetate (PMA) can activate IL33 promoters through protein kinase C in primary airway cells and lines. Transcription factor (TF) binding arrays combined with RNA interference identified activator protein (AP) TFs as regulators of baseline and induced IL33 promoter activity. ATAC-Seq and ChIP-PCR identified chromatin accessibility and differential TF binding as additional control points for transcription from noncanonical promoters. In support of a role for these TFs in COPD pathogenesis, we found that AP-2 (TFAP2A, TFAP2C) and AP-1 (FOS and JUN) family members are upregulated in human COPD specimens. This study implicates integrative and pioneer TFs in regulating IL33 promoters and alternative splicing in human airway basal cells. Our work reveals a potentially novel approach for targeting IL-33 in development of therapeutics for COPD. AUTHORS Heather E. Raphael, Ghandi F. Hassan, Omar A. Osorio, Lucy S. Cohen, Morgan D. Payne, Ella Katz-Kiriakos, Ishana Tata, Jamie Hicks, Derek E. Byers, Bo Zhang, Jen Alexander-Brett × -------------------------------------------------------------------------------- IRON REGULATORY PROTEINS 1 AND 2 HAVE OPPOSING ROLES IN REGULATING INFLAMMATION IN BACTERIAL ORCHITIS Niraj Ghatpande, … , Andreas Meinhardt, Esther G. Meyron-Holtz Niraj Ghatpande, … , Andreas Meinhardt, Esther G. Meyron-Holtz Published February 1, 2024 Citation Information: JCI Insight. 2024;9(5):e175845. https://doi.org/10.1172/jci.insight.175845. View: Text | PDF IRON REGULATORY PROTEINS 1 AND 2 HAVE OPPOSING ROLES IN REGULATING INFLAMMATION IN BACTERIAL ORCHITIS * Text * PDF ABSTRACT Acute bacterial orchitis (AO) is a prevalent cause of intrascrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins 1 and 2 (IRP1 and -2) and these factors are reported to play a role in testicular and immune cell function; however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in less testicular damage and a reduced immune response. Compared with infected wild-type (WT) mice, testes of UPEC-infected Irp1–/– mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast with WT and Irp2–/– mice, no increase in monocytes and neutrophils was detected in testes of Irp1–/– mice upon UPEC infection. Interestingly, in Irp1–/– UPEC-infected testes, we observed an increase in a subpopulation of macrophages (F4/80+CD206+) associated with antiinflammatory and wound-healing activities compared with WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response. AUTHORS Niraj Ghatpande, Aileen Harrer, Bar Azoulay-Botzer, Noga Guttmann-Raviv, Sudhanshu Bhushan, Andreas Meinhardt, Esther G. Meyron-Holtz × -------------------------------------------------------------------------------- CDK1 INHIBITION REDUCES OSTEOGENESIS IN ENDOTHELIAL CELLS IN VASCULAR CALCIFICATION Yan Zhao, … , Kristina I. Boström, Yucheng Yao Yan Zhao, … , Kristina I. Boström, Yucheng Yao Published January 23, 2024 Citation Information: JCI Insight. 2024;9(5):e176065. https://doi.org/10.1172/jci.insight.176065. View: Text | PDF CDK1 INHIBITION REDUCES OSTEOGENESIS IN ENDOTHELIAL CELLS IN VASCULAR CALCIFICATION * Text * PDF ABSTRACT Vascular calcification is a severe complication of cardiovascular diseases. Previous studies demonstrated that endothelial lineage cells transitioned into osteoblast-like cells and contributed to vascular calcification. Here, we found that inhibition of cyclin-dependent kinase (CDK) prevented endothelial lineage cells from transitioning to osteoblast-like cells and reduced vascular calcification. We identified a robust induction of CDK1 in endothelial cells (ECs) in calcified arteries and showed that EC–specific gene deletion of CDK1 decreased the calcification. We found that limiting CDK1 induced E-twenty-six specific sequence variant 2 (ETV2), which was responsible for blocking endothelial lineage cells from undergoing osteoblast differentiation. We also found that inhibition of CDK1 reduced vascular calcification in a diabetic mouse model. Together, the results highlight the importance of CDK1 suppression and suggest CDK1 inhibition as a potential option for treating vascular calcification. AUTHORS Yan Zhao, Yang Yang, Xiuju Wu, Li Zhang, Xinjiang Cai, Jaden Ji, Sydney Chen, Abigail Vera, Kristina I. Boström, Yucheng Yao × -------------------------------------------------------------------------------- PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITION IS AN EFFECTIVE APPROACH FOR THE TREATMENT OF CHEMICAL HEMORRHAGIC CYSTITIS Amanda Wolf-Johnston, … , Edwin K. Jackson, Lori A. Birder Amanda Wolf-Johnston, … , Edwin K. Jackson, Lori A. Birder Published January 25, 2024 Citation Information: JCI Insight. 2024;9(5):e176103. https://doi.org/10.1172/jci.insight.176103. View: Text | PDF PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITION IS AN EFFECTIVE APPROACH FOR THE TREATMENT OF CHEMICAL HEMORRHAGIC CYSTITIS * Text * PDF ABSTRACT Hemorrhagic cystitis may be induced by infection, radiation therapy, or medications or may be idiopathic. Along with hemorrhagic features, symptoms include urinary urgency and frequency, dysuria (painful urination), and visceral pain. Cystitis-induced visceral pain is one of the most challenging types of pain to treat, and an effective treatment would address a major unmet medical need. We assessed the efficacy of a purine nucleoside phosphorylase inhibitor, 8-aminoguanine (8-AG), for the treatment of hemorrhagic/ulcerative cystitis. Lower urinary tract (LUT) function and structure were assessed in adult Sprague-Dawley rats, treated chronically with cyclophosphamide (CYP; sacrificed day 8) and randomized to daily oral treatment with 8-AG (begun 14 days prior to CYP induction) or its vehicle. CYP-treated rats exhibited multiple abnormalities, including increased urinary frequency and neural mechanosensitivity, reduced bladder levels of inosine, urothelial inflammation/damage, and activation of spinal cord microglia, which is associated with pain hypersensitivity. 8-AG treatment of CYP-treated rats normalized all observed histological, structural, biochemical, and physiological abnormalities. In cystitis 8-AG improved function and reduced both pain and inflammation likely by increasing inosine, a tissue-protective purine metabolite. These findings demonstrate that 8-AG has translational potential for reducing pain and preventing bladder damage in cystitis-associated LUT dysfunctions. AUTHORS Amanda Wolf-Johnston, Youko Ikeda, Irina Zabbarova, Anthony J. Kanai, Sheldon Bastacky, Robert Moldwin, Joel N.H. Stern, Edwin K. Jackson, Lori A. Birder × -------------------------------------------------------------------------------- RIGHT VENTRICULAR CARDIOMYOCYTE EXPANSION ACCOMPANIES CARDIAC REGENERATION IN NEWBORN MICE AFTER LARGE LEFT VENTRICULAR INFARCTS Tianyuan Hu, … , Michael I. Kotlikoff, Bernd K. Fleischmann Tianyuan Hu, … , Michael I. Kotlikoff, Bernd K. Fleischmann Published February 6, 2024 Citation Information: JCI Insight. 2024;9(5):e176281. https://doi.org/10.1172/jci.insight.176281. View: Text | PDF RIGHT VENTRICULAR CARDIOMYOCYTE EXPANSION ACCOMPANIES CARDIAC REGENERATION IN NEWBORN MICE AFTER LARGE LEFT VENTRICULAR INFARCTS * Text * PDF ABSTRACT Cauterization of the root of the left coronary artery (LCA) in the neonatal heart on postnatal day 1 (P1) resulted in large, reproducible lesions of the left ventricle (LV), and an attendant marked adaptive response in the right ventricle (RV). The response of both chambers to LV myocardial infarction involved enhanced cardiomyocyte (CM) division and binucleation, as well as LV revascularization, leading to restored heart function within 7 days post surgery (7 dps). By contrast, infarction of P3 mice resulted in cardiac scarring without a significant regenerative and adaptive response of the LV and the RV, leading to subsequent heart failure and death within 7 dps. The prominent RV myocyte expansion in P1 mice involved an acute increase in pulmonary arterial pressure and a unique gene regulatory response, leading to an increase in RV mass and preserved heart function. Thus, distinct adaptive mechanisms in the RV, such as CM proliferation and RV expansion, enable marked cardiac regeneration of the infarcted LV at P1 and full functional recovery. AUTHORS Tianyuan Hu, Mona Malek Mohammadi, Fabian Ebach, Michael Hesse, Michael I. Kotlikoff, Bernd K. Fleischmann × -------------------------------------------------------------------------------- IMPAIRED INNATE AND ADAPTIVE IMMUNE RESPONSES TO BNT162B2 SARS-COV-2 VACCINATION IN SYSTEMIC LUPUS ERYTHEMATOSUS Kavita Y. Sarin, … , Paul J. Utz, Lisa C. Zaba Kavita Y. Sarin, … , Paul J. Utz, Lisa C. Zaba Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e176556. https://doi.org/10.1172/jci.insight.176556. View: Text | PDF IMPAIRED INNATE AND ADAPTIVE IMMUNE RESPONSES TO BNT162B2 SARS-COV-2 VACCINATION IN SYSTEMIC LUPUS ERYTHEMATOSUS * Text * PDF ABSTRACT Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies. AUTHORS Kavita Y. Sarin, Hong Zheng, Yashaar Chaichian, Prabhu S. Arunachalam, Gayathri Swaminathan, Alec Eschholz, Fei Gao, Oliver F. Wirz, Brandon Lam, Emily Yang, Lori W. Lee, Allan Feng, Matthew A. Lewis, Janice Lin, Holden T. Maecker, Scott D. Boyd, Mark M. Davis, Kari C. Nadeau, Bali Pulendran, Purvesh Khatri, Paul J. Utz, Lisa C. Zaba × -------------------------------------------------------------------------------- GNAS AS2 METHYLATION STATUS ENABLES MECHANISM-BASED CATEGORIZATION OF PSEUDOHYPOPARATHYROIDISM TYPE 1B Yorihiro Iwasaki, … , Harald Jüppner, Murat Bastepe Yorihiro Iwasaki, … , Harald Jüppner, Murat Bastepe Published January 30, 2024 Citation Information: JCI Insight. 2024;9(5):e177190. https://doi.org/10.1172/jci.insight.177190. View: Text | PDF GNAS AS2 METHYLATION STATUS ENABLES MECHANISM-BASED CATEGORIZATION OF PSEUDOHYPOPARATHYROIDISM TYPE 1B * Text * PDF ABSTRACT Pseudohypoparathyroidism type 1B (PHP1B) results from aberrant genomic imprinting at the GNAS gene. Defining the underlying genetic cause in new patients is challenging because various genetic alterations (e.g., deletions, insertions) within the GNAS genomic region, including the neighboring STX16 gene, can cause PHP1B, and the genotype-epigenotype correlation has not been clearly established. Here, by analyzing patients with PHP1B with a wide variety of genotypes and epigenotypes, we identified a GNAS differentially methylated region (DMR) of distinct diagnostic value. This region, GNAS AS2, was hypomethylated in patients with genetic alterations located centromeric but not telomeric of this DMR. The AS2 methylation status was captured by a single probe of the methylation-sensitive multiplex ligation–dependent probe amplification (MS-MLPA) assay utilized to diagnose PHP1B. In human embryonic stem cells, where NESP55 transcription regulates GNAS methylation status on the maternal allele, AS2 methylation depended on 2 imprinting control regions (STX16-ICR and NESP-ICR) essential for NESP55 transcription. These results suggest that the AS2 methylation status in patients with PHP1B reflects the position at which the genetic alteration affects NESP55 transcription during an early embryonic period. Therefore, AS2 methylation levels can enable mechanistic PHP1B categorization based on genotype-epigenotype correlation and, thus, help identify the underlying molecular defect in patients. AUTHORS Yorihiro Iwasaki, Monica Reyes, Harald Jüppner, Murat Bastepe × -------------------------------------------------------------------------------- ENDOTHELIAL TDP-43 CONTROLS SPROUTING ANGIOGENESIS AND VASCULAR BARRIER INTEGRITY, AND ITS DELETION TRIGGERS NEUROINFLAMMATION Víctor Arribas, … , Bettina Schmid, Eloi Montanez Víctor Arribas, … , Bettina Schmid, Eloi Montanez Published February 1, 2024 Citation Information: JCI Insight. 2024;9(5):e177819. https://doi.org/10.1172/jci.insight.177819. View: Text | PDF ENDOTHELIAL TDP-43 CONTROLS SPROUTING ANGIOGENESIS AND VASCULAR BARRIER INTEGRITY, AND ITS DELETION TRIGGERS NEUROINFLAMMATION * Text * PDF ABSTRACT TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that regulates gene expression, and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its roles in endothelial cells (ECs), angiogenesis, and vascular function. Using inducible EC-specific TDP-43–KO mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity, and blood vessel stability. Postnatal EC-specific deletion of TDP-43 led to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the CNS with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted the fibronectin matrix around sprouting vessels and reduced β-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature. AUTHORS Víctor Arribas, Yara Onetti, Marina Ramiro-Pareta, Pilar Villacampa, Heike Beck, Mariona Alberola, Anna Esteve-Codina, Angelika Merkel, Markus Sperandio, Ofelia M. Martínez-Estrada, Bettina Schmid, Eloi Montanez × -------------------------------------------------------------------------------- AXL INHIBITION SUPPRESSES EARLY ALLOGRAFT MONOCYTE-TO-MACROPHAGE DIFFERENTIATION AND PROLONGS ALLOGRAFT SURVIVAL Collin Z. Jordan, … , Edward B. Thorp, Xunrong Luo Collin Z. Jordan, … , Edward B. Thorp, Xunrong Luo Published January 23, 2024 Citation Information: JCI Insight. 2024;9(5):e178502. https://doi.org/10.1172/jci.insight.178502. View: Text | PDF AXL INHIBITION SUPPRESSES EARLY ALLOGRAFT MONOCYTE-TO-MACROPHAGE DIFFERENTIATION AND PROLONGS ALLOGRAFT SURVIVAL * Text * PDF ABSTRACT Innate immune cells are important in the initiation and potentiation of alloimmunity in transplantation. Immediately upon organ anastomosis and reperfusion, recipient monocytes enter the graft from circulation and differentiate to inflammatory macrophages to promote allograft inflammation. However, factors that drive their differentiation to inflammatory macrophages are not understood. Here, we show that the receptor tyrosine kinase AXL was a key driver of early intragraft differentiation of recipient infiltrating monocytes to inflammatory macrophages in the presence of allogeneic stimulation and cell-to-cell contact. In this context, the differentiated inflammatory macrophages were capable of efficient alloantigen presentation and allostimulation of T cells of the indirect pathway. Consequently, early and transient AXL inhibition with the pharmacological inhibitor bemcentinib resulted in a profound reduction of initial allograft inflammation and a significant prolongation of allograft survival in a murine heart transplant model. Our results support further investigation of AXL inhibition as part of an induction regimen for transplantation. AUTHORS Collin Z. Jordan, Matthew Tunbridge, Irma Husain, Hiroki Kitai, Miriam E. Dilts, Olivia K. Fay, Koki Abe, Catherine Xiang, Jean Kwun, Tomokazu Souma, Edward B. Thorp, Xunrong Luo × Corrigendum CIRCADIAN REGULATION OF LUNG REPAIR AND REGENERATION Amruta Naik, … , Edward E. Morrisey, Shaon Sengupta Amruta Naik, … , Edward E. Morrisey, Shaon Sengupta Published March 8, 2024 Citation Information: JCI Insight. 2024;9(5):e179745. https://doi.org/10.1172/jci.insight.179745. View: Text | PDF | Amended Article CIRCADIAN REGULATION OF LUNG REPAIR AND REGENERATION * Text * PDF ABSTRACT AUTHORS Amruta Naik, Kaitlyn M. Forrest, Oindrila Paul, Yasmine Issah, Utham K. Valekunja, Soon Y. Tang, Akhilesh B. Reddy, Elizabeth J. Hennessy, Thomas G. Brooks, Fatima Chaudhry, Apoorva Babu, Michael Morley, Jarod A. Zepp, Gregory R. Grant, Garret A. FitzGerald, Amita Sehgal, G. Scott Worthen, David B. Frank, Edward E. Morrisey, Shaon Sengupta × -------------------------------------------------------------------------------- IN-PRESS PREVIEW - MORE INTEGRATED PLASMA PROTEOMICS IDENTIFIES TUBERCULOSIS-SPECIFIC DIAGNOSTIC BIOMARKERS Novel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released... Published March 21, 2024 Clinical Medicine In-Press Preview Infectious disease Pulmonology INTEGRATED PLASMA PROTEOMICS IDENTIFIES TUBERCULOSIS-SPECIFIC DIAGNOSTIC BIOMARKERS * Text * PDF ABSTRACT Novel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections. We applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. Bioinformatic analysis using linear modelling and network correlation analyses identified 118 differentially expressed proteins, significant through three complementary analytical pipelines. Candidate biomarkers were subsequently analysed in two validation cohorts of differing ethnicity using antibody-based proximity extension assays. TB-specific host biomarkers were confirmed. A six-protein diagnostic panel, comprising FETUB, FCGR3B, LRG1, SELL, CD14 and ADA2, differentiated patients with pulmonary TB from healthy controls and patients with other respiratory infections with high sensitivity and specificity in both cohorts. This biomarker panel exceeds the World Health Organisation Target Product Profile specificity criteria for a triage test for TB. The new biomarkers have potential for further development as near-patient TB screening assays, thereby helping to close the case-detection gap that fuels the global pandemic. AUTHORS Hannah F. Schiff, Naomi F. Walker, Cesar Ugarte-Gil, Marc Tebruegge, Antigoni Manousopoulou, Spiros D. Garbis, Salah Mansour, Pak Ho Wong, Gabrielle Rockett, Paolo Piazza, Mahesan Niranjan, Andres F. Vallejo, Christopher H. Woelk, Robert J. Wilkinson, Liku B. Tezera, Diana Garay-Baquero, Paul Elkington × -------------------------------------------------------------------------------- TUMOR TREATING FIELDS SUPPRESS TUMOR CELL GROWTH AND NEUROLOGIC DECLINE IN MODELS OF SPINE METASTASES Spine metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel... Published March 21, 2024 Resource and Technical Advance In-Press Preview Bone biology Neuroscience TUMOR TREATING FIELDS SUPPRESS TUMOR CELL GROWTH AND NEUROLOGIC DECLINE IN MODELS OF SPINE METASTASES * Text * PDF ABSTRACT Spine metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue. We hypothesize bone’s dielectric properties will enhance TTFields mediated suppression of tumor growth in spine metastasis models. Computational modeling of TTFields intensity was performed following surgical resection of a spinal metastasis and demonstrated enhanced TTFields intensity within the resected vertebral body. Additionally, luciferase-tagged human KRIB osteosarcoma and A549 lung adenocarcinoma cell lines were cultured in demineralized bone grafts and exposed to TTFields. Following TTFields exposure, BLI signal decreased 10-80% of baseline while control cultures displayed 4.48-9.36 fold increase in signal. Lastly, TTFields were applied in an orthotopic murine model of spinal metastasis. After 21 days of treatment, control mice demonstrated a 5-fold increase in BLI signal compared to TTFields treated mice. TTFields similarly prevented tumor invasion into the spinal canal and development of neurologic symptoms. Our data suggest that TTFields can be leveraged as a local therapy within minimally-conductive bone of spine metastases. This provides the groundwork for future studies investigating TTFields for patients with treatment-refractory spine metastases. AUTHORS Daniel Ledbetter, Romulo de Almeida, Xizi Wu, Ariel Naveh, Chirag B. Patel, Queena Gonzalez, Thomas H. Beckham, Robert North, Laurence Rhines, Jing Li, Amol Ghia, David Aten, Claudio Tatsui, Christopher Alvarez-Breckenridge × -------------------------------------------------------------------------------- HIPK2 C-TERMINAL DOMAIN INHIBITS NF-ΚB SIGNALING AND RENAL INFLAMMATION IN KIDNEY INJURY HIPK2 is a multifunctional kinase that acts as a key pathogenic mediator of chronic kidney disease and fibrosis. It acts as a central effector of multiple signaling pathways implicated in kidney... Published March 21, 2024 Research In-Press Preview Nephrology HIPK2 C-TERMINAL DOMAIN INHIBITS NF-ΚB SIGNALING AND RENAL INFLAMMATION IN KIDNEY INJURY * Text * PDF ABSTRACT HIPK2 is a multifunctional kinase that acts as a key pathogenic mediator of chronic kidney disease and fibrosis. It acts as a central effector of multiple signaling pathways implicated in kidney injury, such as TGF-β/Smad3-mediated extracellular matrix accumulation, NF-κB-mediated inflammation, and p53-mediated apoptosis. Thus, a better understanding of the specific HIPK2 regions necessary for distinct downstream pathway activation is critical for optimal drug development for CKD. Our study now shows that Caspase 6-mediated removal of the C-terminal region of HIPK2 (HIPK2-CT) leads to hyperactive p65 NF-κB transcriptional response in kidney cells. In contrast, the expression of cleaved HIPK2-CT fragment can restrain p65 NF-κB transcriptional activity by cytoplasmic sequestration NF-κB signaling component, p65 NF-κB, and attenuation of IκBα degradation. Therefore, we examined whether HIPK2-CT expression can be exploited to restrain renal inflammation in vivo. The induction of HIPK2-CT overexpression in kidney tubular cells attenuated p65 nuclear translocation, expression of inflammatory cytokines, and macrophage infiltration in the kidney of mice with unilateral ureteral obstruction and lipopolysaccharide-induced acute kidney injury. Collectively, our findings indicate that the C-terminal region of HIPK2 is involved in the regulation of nuclear NF-κB transcriptional activity and that HIPK2-CT or its analogs could be further exploited as potential anti-inflammatory agents to treat kidney disease. AUTHORS Ye Feng, Zhengzhe Li, Heather Wang, Bi-Cheng Liu, Kyung Lee, John Cijiang He × -------------------------------------------------------------------------------- MAPPING SCA1 REGIONAL VULNERABILITIES REVEALS NEURAL AND SKELETAL MUSCLE CONTRIBUTIONS TO DISEASE Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions... Published March 21, 2024 Research In-Press Preview Neuroscience MAPPING SCA1 REGIONAL VULNERABILITIES REVEALS NEURAL AND SKELETAL MUSCLE CONTRIBUTIONS TO DISEASE * Text * PDF ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. Central nervous system (CNS) contributions to disease were revealed using f-ATXN1146Q/2Q;Nestin-Cre mice, that showed improved rotarod, open field, and Barnes maze performance by 6-12 weeks-of-age. In contrast, striatal contributions to motor deficits using f-ATXN1146Q/2Q;Rgs9-Cre mice revealed that mice lacking ATXN1146Q/2Q in striatal medium-spiny neurons showed a trending improvement in rotarod performance at 30 weeks-of-age. Surprisingly, a prominent role for muscle contributions to disease was revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice based on their recovery from kyphosis and absence of muscle pathology. Collectively, data from the targeted conditional deletion of the expanded allele demonstrated CNS and peripheral contributions to disease and highlighted the need to consider muscle in addition to the brain for optimal SCA1 therapeutics. AUTHORS Lisa Duvick, W. Michael Southern, Kellie A. Benzow, Zoe N. Burch, Hillary P. Handler, Jason S. Mitchell, Hannah Kuivinen, Udaya Gadiparthi, Praseuth Yang, Alyssa Soles, Carrie A. Sheeler, Orion Rainwater, Shannah Serres, Erin B. Lind, Tessa Nichols-Meade, Brennon O'Callaghan, Huda Y. Zoghbi, Marija Cvetanovic, Vanessa C. Wheeler, James M. Ervasti, Michael D. Koob, Harry T. Orr × -------------------------------------------------------------------------------- EVALUATING IMMUNOTHERAPEUTIC OUTCOMES IN TRIPLE NEGATIVE BREAST CANCER WITH A CHOLESTEROL RADIOTRACER IN MICE Evaluating the response to immune checkpoint inhibitors (ICIs) remains an unmet challenge in triple-negative breast cancer (TNBC). The requirement of cholesterol for activation and function of T... Published March 19, 2024 Resource and Technical Advance In-Press Preview Immunology Oncology EVALUATING IMMUNOTHERAPEUTIC OUTCOMES IN TRIPLE NEGATIVE BREAST CANCER WITH A CHOLESTEROL RADIOTRACER IN MICE * Text * PDF ABSTRACT Evaluating the response to immune checkpoint inhibitors (ICIs) remains an unmet challenge in triple-negative breast cancer (TNBC). The requirement of cholesterol for activation and function of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged the PET radiotracer, eFNP-59. eFNP-59 is an analog of cholesterol that our group validated as an imaging biomarker for cholesterol uptake in pre-clinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing ICI-responsive and non-responsive tumors directly, uptake of fluorescent cholesterol and eFNP-59 increased in T cells from ICI-responsive tumors. We discovered that accumulation of cholesterol by T cells increased in ICI-responding tumors that received anti-PD-1 checkpoint immunotherapy. In patients with TNBC, tumors containing cycling T cells had features of cholesterol uptake and trafficking within those populations. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells detects T cell activation and has potential to assess the success of ICI therapy. AUTHORS Nicholas G. Ciavattone, Jenny Nan Guan, Alex Farfel, Jenelle Stauff, Timothy J. Desmond, Benjamin L. Viglianti, Peter J.H. Scott, Allen F. Brooks, Gary D. Luker × -------------------------------------------------------------------------------- VIEW MORE ARTICLES BY TOPIC: Aging AIDS/HIV Angiogenesis Autoimmunity Bone biology Cardiology Cell biology Clinical trials COVID-19 Dermatology Development Endocrinology Gastroenterology Genetics Hematology Hepatology Immunology Infectious disease Inflammation Metabolism Microbiology Muscle biology Nephrology Neuroscience Oncology Ophthalmology Otology Pulmonology Reproductive biology Stem cells Therapeutics Transplantation Vaccines Vascular biology Virology Advertisement SIGN UP FOR EMAIL ALERTS LATEST REVIEWS - MORE THE IMMUNE SYSTEM AND METABOLIC PRODUCTS IN EPILEPSY AND GLIOMA-ASSOCIATED EPILEPSY: EMERGING THERAPEUTIC DIRECTIONS Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are... MUSCLE: AN INDEPENDENT CONTRIBUTOR TO THE NEUROMUSCULAR SPINAL MUSCULAR ATROPHY DISEASE PHENOTYPE Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of... AUTHOR'S TAKE - MORE QUISINOSTAT AS A RADIOSENSITIZER FOR THE TREATMENT OF GLIOBLASTOMA In this episode, Costanza Lo Cascio, Artak Tovmasyan, and Shwetal Mehta discuss the identification of a brain-penetrant HDAC inhibitor with radiosensitizing properties for the treatment of glioblastoma... 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