Issue published November 1, 2024 Previous issue
- Volume 134, Issue 21
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On the cover: Viral infection triggers intestinal dysmotility
Antecedent gastrointestinal infections are thought to trigger intestinal dysmotility. Janova et al. show how T cells responding to a viral infection have adverse consequences for intestinal motility. The cover art shows the myenteric plexus of the middle region of the small intestine stained for West Nile virus (red) and glial marker S100B (green).
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Commentaries
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Abstract
Treatment with T cells genetically engineered to express tumor-reactive T cell receptors (TCRs), known as TCR-gene therapy (TCR-T), is a promising immunotherapeutic approach for patients with cancer. The identification of optimal TCRs to use and tumor antigens to target are key considerations for TCR-T. In this issue of the JCI, Bear and colleagues report on their use of in vitro assays to characterize four HLA-A*03:01– or HLA-A*11:01–restricted TCRs targeting the oncogenic KRAS G12V mutation. The TCRs were derived from healthy donors or patients with pancreatic cancer who had received a vaccine against mutant KRAS. The most promising TCRs warrant testing in patients with KRAS G12V–positive cancers.
Authors
Eric Tran
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Endometriosis, characterized by the presence of endometrial-like tissue outside the uterus, is a condition associated with pain and infertility. In this issue of the JCI, Lv et al. illuminate the critical pathophysiological role of the ten-eleven translocation 3 (TET3) in endometriosis. TET3 expression levels were higher in macrophages of endometriotic lesions compared with control endometrial tissue, implicating TET3 as a contributing factor in the chronic inflammation that occurs in endometriosis. TGF-β1 and MCP1 are present in the peritoneal cavity of women with endometriosis, and macrophage exposure to these factors resulted in upregulation of TET3, thereby promoting their survival. Notably, Bobcat339, a selective TET inhibitor, induced apoptosis in these macrophages. Further, myeloid-specific TET3 loss reduced endometriosis in mice. RNA-Seq analysis following TET3 knockdown revealed alterations in cytokine signaling and cell-death pathways, underscoring the therapeutic potential of targeting TET3 in macrophages as a strategy for managing endometriosis.
Authors
Hossein Hosseinirad, Md Saidur Rahman, Jae-Wook Jeong
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Immature innate and adaptive immunity and vulnerability of narrower airways to obstruction increase the susceptibility of infants to severe respiratory syncytial virus (RSV) disease. In this issue of the JCI, Zhao et al. illustrated greater intrinsic susceptibility of pediatric versus adult airway epithelial cells to RSV-induced cytopathology. Using precision cut lung slices (PCLS) and air-liquid interface (ALI) airway epithelial cell cultures, the authors showed that impaired STAT3 activation in RSV-infected pediatric multiciliated cells increased cell apoptosis and viral shedding, which enhanced the spread of infection. Bolstering STAT3 activation and treatment of neonatal mice with apoptosis inhibitors suppressed virus spread, suggesting that enhancing STAT3 activation may provide therapeutic benefit.
Authors
Raymond J. Pickles, Gang Chen, Scott H. Randell
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Loss of enteric neurons leading to long-term gastrointestinal dysfunction is common to many diseases, and the path to functional recovery is unclear. In this issue of the JCI, Janova et al. report that West Nile virus killed enteric neurons and glia via CD4+ and CD8+ T cells acting through the perforin and Fas ligand pathways. Enteric glial cells contributed to neurogenesis and at least partial replacement of affected neurons. While neurogenesis is important for recovery, dysmotility and disruptions to the network structure persisted. Following enteric injury, the contribution of neurogenesis and the conditions that support restoration of enteric neural circuits for functional recovery remain for further investigation.
Authors
Joel C. Bornstein
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Research Letter
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Abstract
Authors
Hannes Vietzen, Laura M. Kühner, Sarah M. Berger, Philippe L. Furlano, Gabriel Bsteh, Thomas Berger, Paulus Rommer, Elisabeth Puchhammer-Stöckl
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Research Articles
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Abstract
Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune ‘hot’ tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa.
Authors
Sarah Hamze Sinno, Joshua A. Imperatore, Shoumei Bai, Noémie Gomes-Jourdan, Nyasha Mafarachisi, Claudia Coronnello, Linan Zhang, Eldin Jašarević, Hatice U. Osmanbeyoglu, Ronald J. Buckanovich, Sandra Cascio
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Childhood neuroblastoma with MYCN amplification is classified as high risk and often relapses after intensive treatments. Immune checkpoint blockade therapy against the PD-1/L1 axis shows limited efficacy in patients with neuroblastoma, and the cancer intrinsic immune regulatory network is poorly understood. Here, we leverage genome-wide CRISPR/Cas9 screens and identify H2AFY as a resistance gene to the clinically approved PD-1 blocking antibody nivolumab. Analysis of single-cell RNA-Seq datasets reveals that H2AFY mRNA is enriched in adrenergic cancer cells and is associated with worse patient survival. Genetic deletion of H2afy in MYCN-driven neuroblastoma cells reverts in vivo resistance to PD-1 blockade by eliciting activation of the adaptive and innate immunity. Mapping of the epigenetic and translational landscape demonstrates that H2afy deletion promotes cell transition to a mesenchymal-like state. With a multiomics approach, we uncovered H2AFY-associated genes that are functionally relevant and prognostic in patients. Altogether, our study elucidates the role of H2AFY as an epigenetic gatekeeper for cell states and immunogenicity in high-risk neuroblastoma.
Authors
Divya Nagarajan, Rebeca T. Parracho, David Corujo, Minglu Xie, Ginte Kutkaite, Thale K. Olsen, Marta Rubies Bedos, Maede Salehi, Ninib Baryawno, Michael P. Menden, Xingqi Chen, Marcus Buschbeck, Yumeng Mao
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Brain size and cellular heterogeneity are tightly regulated by species-specific proliferation and differentiation of multipotent neural progenitor cells (NPCs). Errors in this process are among the mechanisms of primary hereditary microcephaly (MCPH), a group of disorders characterized by reduced brain size and intellectual disability. Biallelic citron rho-interacting serine/threonine kinase (CIT) missense variants that disrupt kinase function (CITKI/KI) and frameshift loss-of-function variants (CITFS/FS) are the genetic basis for MCPH17; however, the function of CIT catalytic activity in brain development and NPC cytokinesis is unknown. Therefore, we created the CitKI/KI mouse model and found that it did not phenocopy human microcephaly, unlike biallelic CitFS/FS animals. Nevertheless, both Cit models exhibited binucleation, DNA damage, and apoptosis. To investigate human-specific mechanisms of CIT microcephaly, we generated CITKI/KI and CITFS/FS human forebrain organoids. We found that CITKI/KI and CITFS/FS organoids lost cytoarchitectural complexity, transitioning from pseudostratified to simple neuroepithelium. This change was associated with defects that disrupted the polarity of NPC cytokinesis, in addition to elevating apoptosis. Together, our results indicate that both CIT catalytic and scaffolding functions in NPC cytokinesis are critical for human corticogenesis. Species differences in corticogenesis and the dynamic 3D features of NPC mitosis underscore the utility of human forebrain organoid models for understanding human microcephaly.
Authors
Gianmarco Pallavicini, Amanda Moccia, Giorgia Iegiani, Roberta Parolisi, Emily R. Peirent, Gaia Elena Berto, Martina Lorenzati, Rami Y. Tshuva, Alessia Ferraro, Fiorella Balzac, Emilia Turco, Shachi U. Salvi, Hedvig F. Myklebust, Sophia Wang, Julia Eisenberg, Maushmi Chitale, Navjit S. Girgla, Enrica Boda, Orly Reiner, Annalisa Buffo, Ferdinando Di Cunto, Stephanie L. Bielas
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BACKGROUND Neoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes is poorly understood. Here, we explore KRASMUT immunogenicity and the properties of 4 T cell receptors (TCRs) specific for KRASG12V restricted to the HLA-A3 superfamily of class I alleles.METHODS A phase 1 clinical vaccine trial targeting KRASMUT was conducted. TCRs targeting KRASG12V restricted to HLA-A*03:01 or HLA-A*11:01 were isolated from vaccinated patients or healthy individuals. A comprehensive analysis of TCR antigen specificity, affinity, crossreactivity, and CD8 coreceptor dependence was performed. TCR lytic activity was evaluated, and target antigen density was determined by quantitative immunopeptidomics.RESULTS Vaccination against KRASMUT resulted in the priming of CD8+ and CD4+ T cell responses. KRASG12V -specific natural (not affinity enhanced) TCRs exhibited exquisite specificity to mutated protein with no discernible reactivity against KRASWT. TCR-recognition motifs were determined and used to identify and exclude crossreactivity to noncognate peptides derived from the human proteome. Both HLA-A*03:01 and HLA-A*11:01–restricted TCR-redirected CD8+ T cells exhibited potent lytic activity against KRASG12V cancers, while only HLA-A*11:01–restricted TCR-T CD4+ T cells exhibited antitumor effector functions consistent with partial coreceptor dependence. All KRASG12V-specific TCRs displayed high sensitivity for antigen as demonstrated by their ability to eliminate tumor cell lines expressing low levels of peptide/HLA (4.4 to 242) complexes per cell.CONCLUSION This study identifies KRASG12V-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies.TRIAL REGISTRATION ClinicalTrials.gov NCT03592888.FUNDING AACR SU2C/Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, and NIH.
Authors
Adham S. Bear, Rebecca B. Nadler, Mark H. O’Hara, Kelsey L. Stanton, Chong Xu, Robert J. Saporito, Andrew J. Rech, Miren L. Baroja, Tatiana Blanchard, Maxwell H. Elliott, Michael J. Ford, Richard Jones, Shivang Patel, Andrea Brennan, Zachary O’Neil, Daniel J. Powell Jr., Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno
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BACKGROUND Clinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome, and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial.METHODS Whole tumor biopsies from multiple cohorts of patients with advanced prostate cancer were interrogated using whole-exome sequencing (WES), RNA-Seq (bulk and single nucleus), and IHC for RNASEH2B and RB1. Biopsies from patients treated with olaparib in the TOPARP-A and TOPARP-B clinical trials were used to evaluate RNASEH2B clonal selection during olaparib treatment.RESULTS Shallow codeletion of RNASEH2B and adjacent RB1 — colocated at chromosome 13q14 — was common, deep codeletion infrequent, and gene loss associated with lower mRNA expression. In castration-resistant prostate cancer (CRPC) biopsies, RNASEH2B and RB1 mRNA expression correlated, but single nucleus RNA-Seq indicated discordant loss of expression. IHC studies showed that loss of the 2 proteins often occurred independently, arguably due to stochastic second allele loss. Pre- and posttreatment metastatic CRPC (mCRPC) biopsy studies from BRCA1/2 WT tumors, treated on the TOPARP phase II trial, indicated that olaparib eradicated RNASEH2B-loss tumor subclones.CONCLUSION PARP inhibition may benefit men suffering from mCRPC by eradicating tumor subclones with RNASEH2B loss.TRIAL REGISTRATION Clinicaltrials.gov NCT01682772.FUNDING AstraZeneca; Cancer Research UK; Medical Research Council; Cancer Research UK; Prostate Cancer UK; Movember Foundation; Prostate Cancer Foundation.
Authors
Juliet Carmichael, Ines Figueiredo, Bora Gurel, Nick Beije, Wei Yuan, Jan Rekowski, George Seed, Suzanne Carreira, Claudia Bertan, Maria de Los Dolores Fenor de La Maza, Khobe Chandran, Antje Neeb, Jon Welti, Lewis Gallagher, Denisa Bogdan, Mateus Crespo, Ruth Riisnaes, Ana Ferreira, Susana Miranda, Jinqiu Lu, Michael M. Shen, Emma Hall, Nuria Porta, Daniel Westaby, Christina Guo, Rafael Grochot, Christopher J. Lord, Joaquin Mateo, Adam Sharp, Johann de Bono
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Multiple sclerosis (MS) is a chronic disease characterized by dysregulated self-reactive immune responses that damage the neurons’ myelin sheath, leading to progressive disability. The primary therapeutic option, immunosuppressants, inhibits pathogenic anti-myelin responses but depresses the immune system. Antigen-specific monocyte-derived autologous tolerogenic dendritic cells (tolDCs) offer alternative therapeutic approaches to restore tolerance to autoantigens without causing generalized immunosuppression. However, immune dysregulation in MS could impact the properties of the monocytes used as starting material for this cell therapy. Here, we characterized CD14+ monocytes, mature dendritic cells, and vitamin D3–tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HDs). Using multiomics, we identified a switch in these cell types toward proinflammatory features characterized by alterations in the aryl hydrocarbon receptor (AhR) and NF-κB pathways. MS patient–derived VitD3-tolDCs showed reduced tolerogenic properties compared with those from HDs, which were fully restored through direct AhR agonism and by use of in vivo or in vitro dimethyl fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis mouse model, combined therapy of DMF and VitD3-tolDCs was more efficient than monotherapies in reducing the clinical score of mice. We propose that a combined therapy with DMF and VitD3-tolDCs offers enhanced therapeutic potential in treating MS.
Authors
Federico Fondelli, Jana Willemyns, Roger Domenech-Garcia, Maria José Mansilla, Gerard Godoy-Tena, Anna G. Ferreté-Bonastre, Alex Agúndez-Moreno, Silvia Presas-Rodriguez, Cristina Ramo-Tello, Esteban Ballestar, Eva Martínez-Cáceres
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A hexanucleotide GGGGCC repeat expansion in the non-coding region of the C9orf72 gene is the most common genetic mutation identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The resulting repeat RNA and dipeptide repeat proteins from non-conventional repeat translation have been recognized as important markers associated with the diseases. CRISPR/Cas13d, a powerful RNA-targeting tool, has faced challenges in effectively targeting RNA with stable secondary structures. Here we report that CRISPR/Cas13d can be optimized to specifically target GGGGCC repeat RNA. Our results demonstrate that the CRISPR/Cas13d system can be harnessed to significantly diminish the translation of poly-dipeptides originating from the GGGGCC repeat RNA. This efficacy has been validated in various cell types, including induced pluripotent stem cells and differentiated motor neurons originating from C9orf72-ALS patients, as well as in C9orf72 repeat transgenic mice. These findings demonstrate the application of CRISPR/Cas13d in targeting RNA with intricate higher-order structures and suggest a potential therapeutic approach for ALS and FTD.
Authors
Honghe Liu, Xiao-Feng Zhao, Yu-Ning Lu, Lindsey R. Hayes, Jiou Wang
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Dysfunction of group 2 innate lymphoid cells (ILC2s) plays an important role in the development of type 2 inflammation–related diseases such as asthma and pulmonary fibrosis. Notably, neural signals are increasingly recognized as pivotal regulators of ILC2s. However, how ILC2s intrinsically modulate their responsiveness to these neural signals is still largely unknown. Here, using single-cell RNA-Seq, we found that the immune-regulatory molecule phosphatase of activated cells 1 (PAC1) selectively promoted the signaling of the neuropeptide calcitonin gene–related peptide (CGRP) in ILC2s in a cell-intrinsic manner. Genetic ablation of PAC1 in ILC2s substantially impaired the inhibitory effect of CGRP on proliferation and IL-13 secretion. PAC1 deficiency significantly exacerbated allergic airway inflammation induced by Alternaria alternata or papain in mice. Moreover, in human circulating ILC2s, the expression level of PAC1 was also significantly negatively correlated with the number of ILC2s and their expression level of IL13. Mechanistically, PAC1 was necessary for ensuring the expression of CGRP response genes by influencing chromatin accessibility. In summary, our study demonstrated that PAC1 is an important regulator of ILC2 responses, and we propose that PAC1 is a potential target for therapeutic interventions in type 2 inflammation–related diseases.
Authors
Yuan Jin, Bowen Liu, Qiuyu Li, Xiangyan Meng, Xiaowei Tang, Yan Jin, Yuxin Yin
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BACKGROUND Bariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1–3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin.METHODS To identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post–Roux-en-Y gastric bypass (post-RYGB) (n = 10), and nonsurgical controls (n = 8).RESULTS In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone β-hydroxybutyrate were increased by 30%–80% in PBH versus asymptomatic. Conversely, multiple amino acids (branched-chain amino acids, tryptophan) and polyunsaturated lipids were reduced by 20%–50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced 2- to 10-fold in PBH in the fasting state. Postprandially, plasma serotonin was uniquely increased 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin.CONCLUSION Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target.FUNDING National Institutes of Health (NIH) grant R01-DK121995, NIH grant P30-DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo grant 2018/22111-2.
Authors
Rafael Ferraz-Bannitz, Berkcan Ozturk, Cameron Cummings, Vissarion Efthymiou, Pilar Casanova Querol, Lindsay Poulos, Hanna Wang, Valerie Navarrete, Hamayle Saeed, Christopher M. Mulla, Hui Pan, Jonathan M. Dreyfuss, Donald C. Simonson, Darleen A. Sandoval, Mary-Elizabeth Patti
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A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated that antibiotic treatment during influenza infection caused a fungal dysbiosis that drove lung eosinophilia and impaired MRSA clearance. Finally, we evaluated 3 cohorts of hospitalized patients and found that eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs, thereby increasing the risk of developing a secondary bacterial infection.
Authors
Marilia Sanches Santos Rizzo Zuttion, Tanyalak Parimon, Stephanie A. Bora, Changfu Yao, Katherine Lagree, Catherine A. Gao, Richard G. Wunderink, Georgios D. Kitsios, Alison Morris, Yingze Zhang, Bryan J. McVerry, Matthew E. Modes, Alberto M. Marchevsky, Barry R. Stripp, Christopher M. Soto, Ying Wang, Kimberly Merene, Silvia Cho, Blandine L. Victor, Ivan Vujkovic-Cvijin, Suman Gupta, Suzanne L. Cassel, Fayyaz S. Sutterwala, Suzanne Devkota, David M. Underhill, Peter Chen
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Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damaged the enteric nervous system (ENS) and glia, which led to intestinal dysmotility; these T cells used multiple and redundant effector molecules including perforin and Fas ligand. In comparison, WNV-triggered ENS injury and intestinal dysmotility appeared to not require infiltrating monocytes, and damage may have been limited by resident muscularis macrophages. Overall, our experiments support a model in which antigen-specific T cell subsets and their effector molecules responding to WNV infection direct immune pathology against enteric neurons and supporting glia that results in intestinal dysmotility.
Authors
Hana Janova, Fang R. Zhao, Pritesh Desai, Matthias Mack, Larissa B. Thackray, Thaddeus S. Stappenbeck, Michael S. Diamond
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BACKGROUND Most GWAS of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry-enriched protein quantitative loci (pQTL).METHODS We conducted a discovery GWAS of approximately 3,000 plasma proteins measured by the antibody-based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS) and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs was further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome-wide association study (PheWAS) across 2 large multiethnic electronic health record (EHR) systems in All of Us and BioMe.RESULTS We identified 1,002 pQTLs for 925 protein assays. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for cathepsin L (CTSL) and Siglec-9, which were linked with sarcoidosis and non-Hodgkin’s lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, WBC count, and multiple sclerosis.CONCLUSIONS Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.FUNDING NIH K08 HL161445-01A1; 5T32HL160522-03; HHSN268201600034I; HL133870.
Authors
Usman A. Tahir, Jacob L. Barber, Daniel E. Cruz, Meltem Ece Kars, Shuliang Deng, Bjoernar Tuftin, Madeline G. Gillman, Mark D. Benson, Jeremy M. Robbins, Zsu-Zsu Chen, Prashant Rao, Daniel H. Katz, Laurie Farrell, Tamar Sofer, Michael E. Hall, Lynette Ekunwe, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, NHLBI Trans-Omics for Precision Medicine Consortium, Thomas J. Wang, Alex P. Reiner, Pradeep Natarajan, Yuval Itan, Stephen S. Rich, Jerome I. Rotter, James G. Wilson, Laura M. Raffield, Robert E. Gerszten
×Abstract
Endometriosis is a debilitating, chronic inflammatory disease affecting approximately 10% of reproductive-age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we report identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We show that factors from the disease microenvironment upregulated TET3 expression, transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated proinflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival and hence were vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation in both human and mouse macrophages. This degradation was dependent on a von Hippel-Lindau (VHL) E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.
Authors
Haining Lv, Beibei Liu, Yangyang Dai, Feng Li, Stefania Bellone, Yuping Zhou, Ramanaiah Mamillapalli, Dejian Zhao, Muthukumaran Venkatachalapathy, Yali Hu, Gordon G. Carmichael, Da Li, Hugh S. Taylor, Yingqun Huang
×Abstract
The airway surface liquid (ASL) plays a crucial role in lung defense mechanisms, and its composition and volume are regulated by the airway epithelium. The cystic fibrosis transmembrane conductance regulator (CFTR) is abundantly expressed in a rare airway epithelial cell type called an ionocyte. Recently, we demonstrated that ionocytes can increase liquid absorption through apical CFTR and basolateral barttin/chloride channels, while airway secretory cells mediate liquid secretion through apical CFTR channels and basolateral NKCC1 transporters. Th2-driven (IL-4/IL-13) airway diseases, such as asthma, cause goblet cell metaplasia, accompanied by increased mucus production and airway secretions. In this study, we investigate the effect of IL-13 on chloride and liquid transport performed by ionocytes. IL-13 treatment of human airway epithelia was associated with reduced epithelial liquid absorption rates and increased ASL volume. Additionally, IL-13 treatment reduced the abundance of CFTR-positive ionocytes and increased the abundance of CFTR-positive secretory cells. Increasing ionocyte abundance attenuated liquid secretion caused by IL-13. Finally, CFTR-positive ionocytes were less common in asthma and chronic obstructive pulmonary disease and were associated with airflow obstruction. Our findings suggest that loss of CFTR in ionocytes contributes to the liquid secretion observed in IL-13–mediated airway diseases.
Authors
Guillermo S. Romano Ibarra, Lei Lei, Wenjie Yu, Andrew L. Thurman, Nicholas D. Gansemer, David K. Meyerholz, Alejandro A. Pezzulo, Paul B. McCray, Ian M. Thornell, David A. Stoltz
×Abstract
BACKGROUND Recent studies conducted in individuals who survived COVID-19 suggest that SARS-CoV-2 infection is associated with an increased risk of dyslipidemia. However, it remains unclear whether this augmented risk is confirmed in the general population and how this phenomenon is affecting the overall burden of cardiometabolic diseases.METHODS To address these aspects, we conducted a 6-year longitudinal study to examine the broader effects of COVID-19 on dyslipidemia incidence in a real-world population (228,266 individuals) residing in Naples in southern Italy. The pre–COVID-19 and COVID-19 groups were balanced for demographic and clinical factors using propensity score matching.RESULTS Our analysis spans a period of 3 years during the COVID-19 pandemic (2020–2022), comparing dyslipidemia incidence with pre-pandemic data (2017–2019), with a follow-up of at least 1,095 days corresponding to 21,349,215 person-years. During the COVID-19 period, we detected an increased risk of developing any dyslipidemia when compared with the pre–COVID-19 triennium (OR = 1.29; 95% CI, 1.19–1.39). Importantly, these estimates were adjusted for comorbidities by a multivariate analysis.CONCLUSIONS Taken together, our data reveal a notable rise in dyslipidemia incidence during the COVID-19 pandemic, suggesting the utility of establishing specialized clinical monitoring protocols for patients who survive COVID-19 to mitigate the risk of developing dyslipidemia.
Authors
Valentina Trimarco, Raffaele Izzo, Stanislovas S. Jankauskas, Mario Fordellone, Giuseppe Signoriello, Maria Virginia Manzi, Maria Lembo, Paola Gallo, Giovanni Esposito, Roberto Piccinocchi, Francesco Rozza, Carmine Morisco, Pasquale Mone, Gaetano Piccinocchi, Fahimeh Varzideh, Bruno Trimarco, Gaetano Santulli
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Respiratory syncytial virus (RSV) selectively targets ciliated cells in human bronchial epithelium and can cause bronchiolitis and pneumonia, mostly in infants. To identify molecular targets of intervention during RSV infection in infants, we investigated how age regulates RSV interaction with the bronchial epithelium barrier. Employing precision-cut lung slices and air-liquid interface cultures generated from infant and adult human donors, we found robust RSV virus spread and extensive apoptotic cell death only in infant bronchial epithelium. In contrast, adult bronchial epithelium showed no barrier damage and limited RSV infection. Single nuclear RNA-Seq revealed age-related insufficiency of an antiapoptotic STAT3 activation response to RSV infection in infant ciliated cells, which was exploited to facilitate virus spread via the extruded apoptotic ciliated cells carrying RSV. Activation of STAT3 and blockade of apoptosis rendered protection against severe RSV infection in infant bronchial epithelium. Lastly, apoptotic inhibitor treatment of a neonatal mouse model of RSV infection mitigated infection and inflammation in the lung. Taken together, our findings identify a STAT3-mediated antiapoptosis pathway as a target to battle severe RSV disease in infants.
Authors
Caiqi Zhao, Yan Bai, Wei Wang, Gaurang M. Amonkar, Hongmei Mou, Judith Olejnik, Adam J. Hume, Elke Mühlberger, Nicholas W. Lukacs, Rachel Fearns, Paul H. Lerou, Xingbin Ai
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Abstract
Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between ‘borrowed’ and ‘intrinsic’ components. Bioinformatics prioritized one of the ‘borrowed’ components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
Authors
Saptarshi Sinha, Brennan W. Callow, Alex P. Farfel, Suchismita Roy, Siyi Chen, Maria Masotti, Shrila Rajendran, Johanna M. Buschhaus, Celia R. Espinoza, Kathryn E. Luker, Pradipta Ghosh, Gary D. Luker
TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models
Abstract
Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining regulatory T cells (Treg) stability and function, yet the underlying mechanism remains largely unexplored. Here we demonstrate that ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) Treg-specific knockout (Tmed4ΔTreg) mice contain more Treg cells with impaired Foxp3 stability, Treg signature and suppressive activity, which leads to T cell hyperactivation, exacerbated inflammatory phenotype and boosted anti-tumor immunity in mice. Mechanistically, loss of Tmed4 causes defects in ERS and nuclear factor erythroid 2–related factor 2 (NRF2)-related antioxidant response, which results in excessive reactive oxygen species (ROS) that reduces Foxp3 stability and suppressive function of Treg cells in an IRE1α-XBP1 axis-dependent manner. The abnormalities can be effectively rescued by ROS scavenger, NRF2 inducer or forcible expression of IRE1α. Moreover, TMED4 suppresses IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including BIP. Our study reveals that TMED4 maintains Treg cell stability and suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.
Authors
Zhenyan Jiang, Huizi Wang, Xiaoxia Wang, Hongrui Duo, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Hongrui Xiang, Chenyang Guan, Xinyu Wang, Kun Zhang, Peng Zhang, Zhaoyuan Hou, Yong Liu, Zhengting Wang, Bing Su, Bo Li, Youjin Hao, Bin Li, Xuefeng Wu
Abstract
Authors
Andrés R. Muñoz-Rojas, Adam C. Wang, Lisa E. Pomeranz, Elizabeth L. Reizis, Heather W. Stout-Delgado, Ileana C. Miranda, Krishnan Rajagopalan, Tadiwanashe Gwatiringa, Roger R. Fan, Ahmad A. Huda, Neha Maskey, Roseline P. Olumuyide, Aryan S. Patel, Jeffrey M. Friedman, Diane Mathis, Kartik N. Rajagopalan
Abstract
Myocardial infarction (MI) is characterized by massive cardiomyocytes death and cardiac dysfunction, and effective therapies to achieve cardioprotection are sorely needed. Here we reported that flavin containing monooxygenase 2 (FMO2) level was markedly increased in cardiomyocytes both in ex vivo and in vivo models of ischemia injury. Genetic deletion of FMO2 resulted in reduced cardiomyocyte survival and enhanced cardiac dysfunction, whereas cardiomyocyte-specific FMO2 overexpression exerted a protective effect in infarcted rat hearts. Mechanistically, FMO2 inhibited the activation of endoplasmic reticulum (ER) stress-induced apoptotic proteins, including caspase 12 and C/EBP homologous protein (CHOP), by down-regulating unfolded protein response (UPR) pathway. Furthermore, we identified FMO2 as a chaperone that catalyzed disulfide-bond formation in unfolded/misfolded proteins through its GVSG motif. GVSG-mutated FMO2 failed to catalyze disulfide-bond formation and lost its protection against ER stress and cardiomyocyte death. Finally, we demonstrated the protective effect of FMO2 in human induced pluripotent stem cell–derived cardiomyocyte (hiPSC-CM) model. Collectively, this study highlights FMO2 as a key modulator of oxidative protein folding in cardiomyocytes and underscores its therapeutic potential for treating ischemic heart disease.
Authors
Qingnian Liu, Jiniu Huang, Hao Ding, Yue Tao, Jinliang Nan, Changchen Xiao, Yingchao Wang, Rongrong Wu, Cheng Ni, Zhiwei Zhong, Wei Zhu, Jinghai Chen, Chenyun Zhang, Xiao He, Danyang Xiong, Xinyang Hu, Jian'an Wang
Abstract
BACKGROUND. Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment. METHODS. We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5–7.99 years; n = 433) and short-term survivors (STS; 2–4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content. RESULTS. Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSIONS. The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING. Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.
Authors
Brad H. Nelson, Phineas T. Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald L.I. Stevens, Shreena Kalaria, Karanvir Singh, Céline M. Laumont, Elena Moss, Aliya Alimujiang, Nicola S. Meagher, Adelyn Bolithon, Sian Fereday, Catherine J. Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L. Goode, Anthony N. Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A. Doherty, Holly R. Harris, Kara L. Cushing-Haugen, Michael S. Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E. Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul D.P. Pharoah, Jessica Boros, Alison H. Brand, Paul R. Harnett, Raghwa Sharma, Jonathan L. Hecht, Naoko Sasamoto, Kathryn L. Terry, Beth Y. Karlan, Jenny Lester, Michael E. Carney, Marc T. Goodman, Brenda Y. Hernandez, Lynne R. Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A. Fasching, Christiani Bisinotto, Francisco José Candido dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S. Cook, Nhu D. Le, Aleksandra Gentry-Maharaj, Usha Menon, María J. García, Cristina Rodriguez-Antona, Kyo M. Farrington, Linda E. Kelemen, Stefan Kommoss, Annette Staebler, Dale W. Garsed, James D. Brenton, Anna M. Piskorz, David D.L. Bowtell, Anna DeFazio, Susan J. Ramus, Malcolm C. Pike, Celeste Leigh Pearce
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