Issue published September 17, 2024 Previous issue
- Volume 134, Issue 18
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On the cover: Defining the immune and epithelial cell network that responds to lung injury
Wu et al. report an immune niche with monocyte-derived dendritic cells (moDCs) that supplies growth factor GPNMB to CD44 receptor on basal-epithelial stem cells to drive post-viral lung disease. The cover image shows moDCs costaining for GPNMB (green) and CD11c (red), with DAPI counterstaining (blue), in structural remodeling regions in mouse lung after respiratory viral infection. Image credit: Kangyun Wu.
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100th Anniversary Viewpoint
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Abstract
Authors
Mesude Bicak, Cansu Cimen Bozkus, Nina Bhardwaj
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Review Series
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Abstract
Depression and multiple musculoskeletal disorders are overrepresented in women compared with men. Given that depression is a modifiable risk factor and improvement of depressive symptoms increases positive outcomes following orthopedic intervention, efforts to improve clinical recognition of depressive symptoms and increased action toward ameliorating depressive symptoms among orthopedic patients are positioned to reduce complications and positively affect patient-reported outcomes. Although psychosocial factors play a role in the manifestation and remittance of depression, it is also well appreciated that primary biochemical changes are capable of causing and perpetuating depression. Unique insight for novel treatments of depression may be facilitated by query of the bidirectional relationship between musculoskeletal health and depression. This Review aims to synthesize the diverse literature on sex, depression, and orthopedics and emphasize the potential for common underlying biological substrates. Given the overrepresentation of depression and musculoskeletal disorders among women, increased emphasis on the biological drivers of the co-occurrence of these disorders is positioned to improve women’s health.
Authors
Mackenzie Newman, Henry J. Donahue, Gretchen N. Neigh
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Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.
Authors
Erin Mihealsick, Anna Word, Eileen P. Scully
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Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.
Authors
DeLisa Fairweather, Danielle J. Beetler, Elizabeth J. McCabe, Scott M. Lieberman
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Commentaries
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Abstract
Fibrosis is a common manifestation of most progressive and degenerative diseases, with myofibroblast activation and matrix accumulation playing a key role. In this issue of the JCI, Hoeft et al. identify the important role of ADAMTS12 in fibroblast activation. ADAMTS12, a secreted protein, is involved in extracellular matrix (ECM) remodeling, cell signaling, and inflammation. ADAMTS12 facilitates proteolysis by cleaving various substrates such as ECM components, which are vital for cellular signaling and remodeling. Additionally, it modulates cell-matrix interactions, influencing cell adhesion and migration, and plays an important role in the inflammatory processes. Understanding the role of ADAMTS12 offers potential therapeutic insights for targeting fibrosis in progressive diseases.
Authors
Bernhard Dumoulin, Katalin Susztak
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Epigallocatechin gallate (EGCG) is a polyphenol plant metabolite abundant in tea that has demonstrated antifibrotic properties in the lung. In this issue of the JCI, Cohen, Brumwell, and colleagues interrogated the mechanistic action of EGCG by investigating lung biopsies of patients with mild interstitial lung disease (ILD) who had undergone EGCG treatment. EGCG targeted the WNT inhibitor SFRP2, which was enriched in fibrotic fibroblasts and acted as a TGF-β target, with paracrine effects leading to pathologic basal metaplasia of alveolar epithelial type 2 cells. This study emphasizes the epithelial-mesenchymal trophic unit as a central signaling hub in lung fibrosis. Understanding and simultaneous targeting of interlinked signaling pathways, such as TGF-β and WNT, paves the road for future treatment options for pulmonary fibrosis.
Authors
Olivier Burgy, Melanie Königshoff
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Microbial mimicry, the process in which a microbial antigen elicits an immune response and breaks tolerance to a structurally related self-antigen, has long been proposed as a mechanism in autoimmunity. In this issue of the JCI, Dolton et al. extend this paradigm by demonstrating that a naturally processed peptide from Klebsiella oxytoca acts as a superagonist for autoreactive T cells in type 1 diabetes (T1D). Reframing microbial mimics as superagonists that are thousands of times better at binding disease-associated autoreactive T cell receptors than self-peptides serves to narrow the search space for relevant sequences in the vast microbial proteome. Moreover, the identified superagonists have implications for the intervention and personalized monitoring of T1D that may carry over to other autoimmune diseases with microbial mimicry.
Authors
Jesusa Capera, Michael L. Dustin
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Intestinal fibrosis is a severe complication of Crohn’s disease, often requiring surgical intervention. Despite extensive research efforts, an effective treatment to prevent or reverse intestinal fibrosis remains elusive. In this issue of the JCI, Zhang, Wang, and colleagues employed single-cell RNA sequencing to uncover mechanisms of the fibrotic process. They identified a key fibroblast subset of TWIST1+FAP+ cells that interacts with CXCL9+ macrophages. TWIST1 emerged as a central regulator of the fibrotic microenvironment, representing a promising therapeutic target for effectively treating intestinal fibrosis.
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Giovanni Santacroce, Antonio Di Sabatino
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Research Letters
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Abstract
Authors
Benjamin J. Landis, Benjamin M. Helm, Matthew D. Durbin, Lindsey R. Helvaty, Jeremy L. Herrmann, Michael Johansen, Gabrielle C. Geddes, Stephanie M. Ware
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Authors
Shruti Gupta, Olivia Green-Lingren, Sudhir Bhimaniya, Aleksandra Krokhmal, Heather Jacene, Marlies Ostermann, Sugama Chicklore, Ben Sprangers, Christophe M. Deroose, Sandra M. Herrmann, Sophia L. Wells, Sarah A. Kaunfer, Jessica L. Ortega, Clara García-Carro, Michael Bold, Kevin L. Chen, Meghan E. Sise, Pedram Heidari, Wai Lun Will Pak, Meghan D. Lee, Pazit Beckerman, Yael Eshet, Raymond K. Hsu, Miguel Hernandez Pampaloni, Arash Rashidi, Norbert Avril, Vicki Donley, Zain Mithani, Russ Kuker, Muhammad O Awiwi, Mindy X. Wang, Sujal I. Shah, Michael D. Weintraub, Heiko Schoder, Raad B. Chowdhury, Harish Seethapathy, Kerry L. Reynolds, Maria Jose Soler, Ala Abudayyeh, Ilya Glezerman, David E. Leaf
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Research Articles
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Abstract
CD8+ T cells destroy insulin-producing pancreatic β cells in type 1 diabetes through HLA class I–restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02–peptide–TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24+ healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease.
Authors
Garry Dolton, Anna Bulek, Aaron Wall, Hannah Thomas, Jade R. Hopkins, Cristina Rius, Sarah A.E. Galloway, Thomas Whalley, Li Rong Tan, Théo Morin, Nader Omidvar, Anna Fuller, Katie Topley, Md Samiul Hasan, Shikha Jain, Nirupa D’Souza, Thomas Hodges-Hoyland, the TIRID Consortium, Owen B. Spiller, Deborah Kronenberg-Versteeg, Barbara Szomolay, Hugo A. van den Berg, Lucy C. Jones, Mark Peakman, David K. Cole, Pierre J. Rizkallah, Andrew K. Sewell
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Patients affected by glioma frequently experience epileptic discharges; however, the causes of brain tumor–related epilepsy (BTRE) are still not completely understood. We investigated the mechanisms underlying BTRE by analyzing the effects of exosomes released by U87 glioma cells and by patient-derived glioma cells. Rat hippocampal neurons incubated for 24 hours with these exosomes exhibited increased spontaneous firing, while their resting membrane potential shifted positively by 10–15 mV. Voltage clamp recordings demonstrated that the activation of the Na+ current shifted toward more hyperpolarized voltages by 10–15 mV. To understand the factors inducing hyperexcitability, we focused on exosomal cytokines. Western blot and ELISAs showed that TNF-α was present inside glioma-derived exosomes. Remarkably, incubation with TNF-α fully mimicked the phenotype induced by exosomes, with neurons firing continuously, while their resting membrane potential shifted positively. Real-time PCR revealed that both exosomes and TNF-α induced overexpression of the voltage-gated Na+ channel Nav1.6, a low-threshold Na+ channel responsible for hyperexcitability. When neurons were preincubated with infliximab, a specific TNF-α inhibitor, the hyperexcitability induced by exosomes and TNF-α was drastically reduced. We propose that infliximab, an FDA-approved drug to treat rheumatoid arthritis, could ameliorate the conditions of glioma patients with BTRE.
Authors
Cesar Adolfo Sanchez Trivino, Renza Spelat, Federica Spada, Camilla D’Angelo, Ivana Manini, Irene Giulia Rolle, Tamara Ius, Pietro Parisse, Anna Menini, Daniela Cesselli, Miran Skrap, Fabrizia Cesca, Vincent Torre
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NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, as linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ–KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV rechallenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2 immunity, typified by a higher IgG4/IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation, and long-term protection from secondary homologous and heterologous infections in mice, with consistent associations observed in humans. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.
Authors
Youngjoo Choi, Wilfried A.A. Saron, Aled O’Neill, Manouri Senanayake, Annelies Wilder-Smith, Abhay P.S. Rathore, Ashley L. St. John
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Maintaining protein homeostasis (proteostasis) requires precise control of protein folding and degradation. Failure to properly respond to stresses disrupts proteostasis, which is a hallmark of many diseases, including cataracts. Hibernators are natural cold-stress adaptors; however, little is known about how they keep a balanced proteome under conditions of drastic temperature shift. Intriguingly, we identified a reversible lens opacity phenotype in ground squirrels (GSs) associated with their hibernation-rewarming process. To understand this “cataract-reversing” phenomenon, we first established induced lens epithelial cells differentiated from GS-derived induced pluripotent stem cells, which helped us explore the molecular mechanism preventing the accumulation of protein aggregates in GS lenses. We discovered that the ubiquitin-proteasome system (UPS) played a vital role in minimizing the aggregation of the lens protein αA-crystallin (CRYAA) during rewarming. Such function was, for the first time to our knowledge, associated with an E3 ubiquitin ligase, RNF114, which appears to be one of the key mechanisms mediating the turnover and homeostasis of lens proteins. Leveraging this knowledge gained from hibernators, we engineered a deliverable RNF114 complex and successfully reduced lens opacity in rats with cold-induced cataracts and zebrafish with oxidative stress–related cataracts. These data provide new insights into the critical role of the UPS in maintaining proteostasis in cold and possibly other forms of stresses. The newly identified E3 ubiquitin ligase RNF114, related to CRYAA, offers a promising avenue for treating cataracts with protein aggregates.
Authors
Hao Yang, Xiyuan Ping, Jiayue Zhou, Hailaiti Ailifeire, Jing Wu, Francisco M. Nadal-Nicolás, Kiyoharu J. Miyagishima, Jing Bao, Yuxin Huang, Yilei Cui, Xin Xing, Shiqiang Wang, Ke Yao, Wei Li, Xingchao Shentu
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Fibrosis represents the uncontrolled replacement of parenchymal tissue with extracellular matrix (ECM) produced by myofibroblasts. While genetic fate-tracing and single-cell RNA-Seq technologies have helped elucidate fibroblast heterogeneity and ontogeny beyond fibroblast to myofibroblast differentiation, newly identified fibroblast populations remain ill defined, with respect to both the molecular cues driving their differentiation and their subsequent role in fibrosis. Using an unbiased approach, we identified the metalloprotease ADAMTS12 as a fibroblast-specific gene that is strongly upregulated during active fibrogenesis in humans and mice. Functional in vivo KO studies in mice confirmed that Adamts12 was critical during fibrogenesis in both heart and kidney. Mechanistically, using a combination of spatial transcriptomics and expression of catalytically active or inactive ADAMTS12, we demonstrated that the active protease of ADAMTS12 shaped ECM composition and cleaved hemicentin 1 (HMCN1) to enable the activation and migration of a distinct injury-responsive fibroblast subset defined by aberrant high JAK/STAT signaling.
Authors
Konrad Hoeft, Lars Koch, Susanne Ziegler, Ling Zhang, Steffen Luetke, Maria C. Tanzer, Debashish Mohanta, David Schumacher, Felix Schreibing, Qingqing Long, Hyojin Kim, Barbara M. Klinkhammer, Carla Schikarski, Sidrah Maryam, Mathijs Baens, Juliane Hermann, Sarah Krieg, Fabian Peisker, Laura De Laporte, Gideon J.L. Schaefer, Sylvia Menzel, Joachim Jankowski, Benjamin D. Humphreys, Adam Wahida, Rebekka K. Schneider, Matthias Versele, Peter Boor, Matthias Mann, Gerhard Sengle, Sikander Hayat, Rafael Kramann
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Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin–like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.
Authors
Wenyan Ren, Weiqi Hong, Jingyun Yang, Jun Zou, Li Chen, Yanan Zhou, Hong Lei, Aqu Alu, Haiying Que, Yanqiu Gong, Zhenfei Bi, Cai He, Minyang Fu, Dandan Peng, Yun Yang, Wenhai Yu, Cong Tang, Qing Huang, Mengli Yang, Bai Li, Jingmei Li, Junbin Wang, Xuelei Ma, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Jiong Li, Wei Wang, Guangwen Lu, Guobo Shen, Li Yang, Jinliang Yang, Zhenling Wang, Guowen Jia, Zhaoming Su, Bin Shao, Hanpei Miao, Johnson Yiu-Nam Lau, Yuquan Wei, Kang Zhang, Lunzhi Dai, Shuaiyao Lu, Xiawei Wei
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Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGF-β1 signaling inhibitor epigallocatechin gallate (EGCG) to interstitial lung disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA-Seq on spare tissue. Biopsies from untreated patients showed higher fibroblast TGF-β1 signaling compared with nondisease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGF-β1 signaling and several proinflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzled-related protein 2 (sFRP2), an unrecognized TGF-β1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision-cut lung slices (PCLSs) from nondiseased donors, we found TGF-β1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature cytokeratin 5+ (Krt5+) basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGF-β1 signaling in ILD and the therapeutic potential of EGCG in reducing idiopathic pulmonary fibrosis–related (IPF-related) transcriptional changes and identify TGF-β1/noncanonical Wnt pathway crosstalk via sFRP2 as a mechanism for dysfunctional epithelial signaling in IPF/ILD.
Authors
Max L. Cohen, Alexis N. Brumwell, Tsung Che Ho, Kiana Garakani, Genevieve Montas, Darren Leong, Vivianne W. Ding, Jeffrey A. Golden, Binh N. Trinh, David M. Jablons, Michael A. Matthay, Kirk D. Jones, Paul J. Wolters, Ying Wei, Harold A. Chapman, Claude Jourdan Le Saux
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The study of transcription factors that determine specialized neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electrophysiologically excitable cells that link the oxygen concentration of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by type I cells of the carotid body, and recent work has revealed one isoform of the hypoxia-inducible transcription factor (HIF), HIF-2α, as having a nonredundant role in the development and function of that organ. Here, we show that activation of HIF-2α, including isolated overexpression of HIF-2α but not HIF-1α, is sufficient to induce oxygen chemosensitivity in adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues resembling the fetal organ of Zuckerkandl, which also manifests oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of gene classes that are ordinarily characteristic of the carotid body, including G protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking 2 major oxygen-sensing systems.
Authors
Maria Prange-Barczynska, Holly A. Jones, Yoichiro Sugimoto, Xiaotong Cheng, Joanna D.C.C. Lima, Indrika Ratnayaka, Gillian Douglas, Keith J. Buckler, Peter J. Ratcliffe, Thomas P. Keeley, Tammie Bishop
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Strategies beyond hormone-related therapy need to be developed to improve prostate cancer mortality. Here, we show that FUBP1 and its methylation were essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppressed the development of prostate cancer. FUBP1 accelerated prostate cancer development in various preclinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence in our patient cohort. Suppressed prostate cancer progression was observed in various genetic mouse models expressing the FUBP1 mutant deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in various preclinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potential therapeutic strategy for prostate cancer management.
Authors
Weiwei Yan, Xun Liu, Xuefeng Qiu, Xuebin Zhang, Jiahui Chen, Kai Xiao, Ping Wu, Chao Peng, Xiaolin Hu, Zengming Wang, Jun Qin, Liming Sun, Luonan Chen, Denglong Wu, Shengsong Huang, Lichen Yin, Zhenfei Li
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Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase 2 (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart, predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knockout mice and mature human induced pluripotent stem cell–derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.
Authors
Arvind Sridhar, Jaime DeSantiago, Hanna Chen, Mahmud Arif Pavel, Olivia Ly, Asia Owais, Miles Barney, Jordan Jousma, Sarath Babu Nukala, Khaled Abdelhady, Malek Massad, Lona Ernst Rizkallah, Sang-Ging Ong, Jalees Rehman, Dawood Darbar
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BACKGROUND Frailty significantly affects morbidity and mortality rates in the older population (age >65 years). Age-related degenerative diseases are influenced by the intestinal microbiota. However, limited research exists on alterations in the intestinal microbiota in frail older individuals, and the effectiveness of prebiotic intervention for treating frailty remains uncertain.OBJECTIVE We sought to examine the biological characteristics of the intestinal microbiome in frail older individuals and assess changes in both frailty status and gut microbiota following intervention with a prebiotic blend consisting of inulin and oligofructose.METHODS The study consisted of 3 components: an observational analysis with a sample size of 1,693, a cross-sectional analysis (n = 300), and a multicenter double-blind, randomized, placebo-controlled trial (n = 200). Body composition, commonly used scales, biochemical markers, intestinal microbiota, and metabolites were examined in 3 groups of older individuals (nonfrail, prefrail, and frail). Subsequently, changes in these indicators were reevaluated after a 3-month intervention using the prebiotic mixture for the prefrail and frail groups.RESULTS The intervention utilizing a combination of prebiotics significantly improved frailty and renal function among the older population, leading to notable increases in protein levels, body fat percentage, walking speed, and grip strength. Additionally, it stimulated an elevation in gut probiotic count and induced alterations in microbial metabolite expression levels as well as corresponding metabolic pathways.CONCLUSIONS The findings suggest a potential link between changes in the gut microbiota and frailty in older adults. Prebiotics have the potential to modify the gut microbiota and metabolome, resulting in improved frailty status and prevention of its occurrence.TRIAL REGISTRATION ClinicalTrials.gov NCT03995342.
Authors
Jie Yang, Liming Hou, Anhui Wang, Lei Shang, Xin Jia, Rong Xu, Xiaoming Wang
×Abstract
BACKGROUND Teplizumab, a non-FcR-binding anti-CD3 mAb, is approved to delay progression of type 1 diabetes (T1D) in at-risk patients. Previous investigations described the immediate effects of the 14-day treatment, but longer-term effects of the drug remain unknown.METHODS With an extended analysis of study participants, we found that 36% were undiagnosed or remained free of clinical diabetes after 5 years, suggesting operational tolerance. Using single-cell RNA sequencing, we compared the phenotypes, transcriptome, and repertoire of peripheral blood CD8+ T cells including autoreactive T cells from study participants before and after teplizumab and features of responders and non-responders.RESULTS At 3 months, there were transcriptional signatures of cell activation in CD4+ and CD8+ T cells including signaling that was reversed at 18 months. At that time, there was reduced expression of genes in T cell receptor and activation pathways in clinical responders. In CD8+ T cells, we found increased expression of genes associated with exhaustion and immune regulation with teplizumab treatment. These transcriptional features were further confirmed in an independent cohort. Pseudotime analysis showed differentiation of CD8+ exhausted and memory cells with teplizumab treatment. IL7R expression was reduced, and patients with lower expression of CD127 had longer diabetes-free intervals. In addition, the frequency of autoantigen-reactive CD8+ T cells, which expanded in the placebo group over 18 months, did not increase in the teplizumab group.CONCLUSION These findings indicate that teplizumab promotes operational tolerance in T1D, involving activation followed by exhaustion and regulation, and prevents expansion of autoreactive T cells.TRIAL REGISTRATION ClinicalTrials.gov NCT01030861.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases/NIH, Juvenile Diabetes Research Foundation.
Authors
Ana Lledó-Delgado, Paula Preston-Hurlburt, Sophia Currie, Pamela Clark, Peter S. Linsley, S. Alice Long, Can Liu, Galina Koroleva, Andrew J. Martins, John S. Tsang, Kevan C. Herold
×Abstract
Intestinal fibrosis, a severe complication of Crohn’s disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective antifibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-Seq) of fibrotic and nonfibrotic ileal tissues from patients with CD with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset FAP+ fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomic profiling of chronic dextran sulfate sodium salt murine colitis model revealed that CD81+Pi16– fibroblasts exhibited transcriptomic and functional similarities to human FAP+ fibroblasts. Consistently, FAP+ fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by FAP+ fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by CXCL9+ macrophages enriched in fibrotic tissues via IL-1β and TGF-β signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment.
Authors
Yao Zhang, Jiaxin Wang, Hongxiang Sun, Zhenzhen Xun, Zirui He, Yizhou Zhao, Jingjing Qi, Sishen Sun, Qidi Yang, Yubei Gu, Ling Zhang, Chunhua Zhou, Youqiong Ye, Ningbo Wu, Duowu Zou, Bing Su
×Abstract
T cell–based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.
Authors
Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H. Wood, Devina D. Lakhiani, Abate A. Bashaw, Lisa M. Nilsson, Ji Li, Edward R. Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair R.R. Forrest, Suraj Sakaram, Rafael Carretero, Günter J. Hämmerling, Jonas A. Nilsson, Gabriel Y.F. Lee, Ruth Ganss
×Abstract
The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.
Authors
Daniel Westaby, Juan M. Jiménez-Vacas, Ines Figueiredo, Jan Rekowski, Claire Pettinger, Bora Gurel, Arian Lundberg, Denisa Bogdan, Lorenzo Buroni, Antje Neeb, Ana Padilha, Joe Taylor, Wanting Zeng, Souvik Das, Emily Hobern, Ruth Riisnaes, Mateus Crespo, Susana Miranda, Ana Ferreira, Brian P. Hanratty, Daniel Nava Rodrigues, Claudia Bertan, George Seed, Maria de Los Dolores Fenor de La Maza, Christina Guo, Juliet Carmichael, Rafael Grochot, Khobe Chandran, Anastasia Stavridi, Andreas Varkaris, Nataly Stylianou, Brett G. Hollier, Nina Tunariu, Steven P. Balk, Suzanne Carreira, Wei Yuan, Peter S. Nelson, Eva Corey, Michael Haffner, Johann de Bono, Adam Sharp
×Abstract
Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provided long-lasting correction of reprogramming and broad disease phenotypes. These same control points worked directly in mouse and human basal ESC organoids. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury.
Authors
Kangyun Wu, Yong Zhang, Huiqing Yin-DeClue, Kelly Sun, Dailing Mao, Kuangying Yang, Stephen R. Austin, Erika C. Crouch, Steven L. Brody, Derek E. Byers, Christy M. Hoffmann, Michael E. Hughes, Michael J. Holtzman
×Abstract
BACKGROUND Metastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODS Our prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTS Patients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSION These data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDING National Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.
Authors
Nima Sharifi, Robert Diaz, Hui-Ming Lin, Evan Roberts, Lisa G. Horvath, Andrew Martin, Martin R. Stockler, Sonia Yip, Vinod V. Subhash, Neil Portman, Ian D. Davis, Christopher J. Sweeney
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Abstract
A hexanucleotide GGGGCC repeat expansion in the non-coding region of 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
Abstract
BACKGROUND. Neoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes are poorly understood. Here, we explore KRASMUT immunogenicity and the properties of 4 TCRs specific for KRASG12V restricted to HLA-A3 superfamily of class I alleles. METHODS. A phase I 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, cross-reactivity, 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 discernable reactivity against KRASWT. TCR-recognition motifs were determined and used to identify and exclude cross-reactivity to non-cognate 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 anti-tumor effector functions consistent with partial co-receptor dependence. All KRASG12V-specific TCRs displayed high sensitivity for antigen as demonstrated by their ability to eliminate tumor cell lines expressing low levels of 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 (R01 CA204261, P01 CA217805, P30 CA016520).
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 C. Jones, Shivang Patel, Andrea L. Brennan, Zachary O'Neil, Daniel J. Powell Jr., Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno
Abstract
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 auto-antigens 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 (mDCs) and Vitamin-D3-tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HD). Using multi-omics, we identified a switch in these cell types towards proinflammatory features characterized by alterations in the AhR and NF-kB pathways. MS patient-derived VitD3-tolDCs showed reduced tolerogenic properties compared to those from HD, which were fully restored through direct AhR agonism and using in vivo or in vitro Dimethyl Fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis (EAE) 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
Abstract
Dysfunction of group II innate lymphoid cells (ILC2s) plays an important role in the development of type II 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 sequencing, we found that the immune regulatory molecule PAC1 (phosphatase of activated cells 1) selectively promotes the signaling of neuropeptide CGRP (calcitonin gene-related peptide) in ILC2s through 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 cell amount and the 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 proposed that PAC1 is a potential target for therapeutic interventions of type II inflammation-related diseases.
Authors
Yuan Jin, Bowen Liu, Qiuyu Li, Xiangyan Meng, Xiaowei Tang, Yan Jin, Yuxin Yin
Abstract
Current research reports that lactate affects Treg metabolism, although the precise mechanism has only been partially elucidated. In this study, we presented evidence demonstrating that elevated lactate levels enhanced cell proliferation, suppressive capabilities, and oxidative phosphorylation (OXPHOS) in human Tregs. The expression levels of Monocarboxylate Transporters 1/2/4 (MCT1/2/4) regulate intracellular lactate concentration, thereby influencing the varying responses observed in naive Tregs and memory Tregs. Through mitochondrial isolation, sequencing, and analysis of human Tregs, we determined that Alpha-1,3-Mannosyl-Glycoprotein 2-Beta-N-Acetylglucosaminyltransferase (MGAT1) served as the pivotal driver initiating downstream N-glycosylation events involving progranulin (GRN) and hypoxia-upregulated 1 (HYOU1), consequently enhancing Treg OXPHOS. The mechanism by which MGAT1 was upregulated in mitochondria depended on elevated intracellular lactate that promoted the activation of XBP1s, which, in turn, supported MGAT1 transcription as well as the interaction of lactate with the translocase of the mitochondrial outer membrane 70 (TOM70) import receptor, facilitating MGAT1 translocation into mitochondria. Pre-treatment of Tregs with lactate reduced mortality in a xenogeneic graft-versus-host disease (GvHD) model. Together, these findings underscored the active regulatory role of lactate in human Treg metabolism through the upregulation of MGAT1 transcription and its facilitated translocation into the mitochondria.
Authors
Jinren Zhou, Jian Gu, Qufei Qian, Yigang Zhang, Tianning Huang, Xiangyu Li, Zhuoqun Liu, Qing Shao, Yuan Liang, Lei Qiao, Xiaozhang Xu, Qiuyang Chen, Zibo Xu, Yu Li, Ji Gao, Yufeng Pan, Yiming Wang, Roddy O'Connor, Keli L. Hippen, Ling Lu, Bruce R. Blazar
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