Issue published December 2, 2024 Previous issue
On the cover: Epidermal stem cells controlling hair formation
In this study, Ghotbi et al. identify transcription factor Krox20 as a marker of an epidermal stem cell population that is indispensable for hair formation and regeneration, as in vivo deletion of this population results in hair loss. In the cover image, the spheres within the strands of healthy hair represent stem cell reservoirs derived from KROX20-positive cells that are necessary for hair growth. Image credit: Renee McKay/Microsoft Designer
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Commentaries
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Abstract
Sex-based differences in autoimmune disease susceptibility have long been recognized, prompting investigations into how sex hormones influence immunity. Recent advances suggest that hormones may shape immune responses by altering cellular metabolism. In this issue of the JCI, Chowdhury et al. authenticates this model, showing that androgen receptor signaling modulates T helper 17 (Th17) cell metabolism, specifically glutaminolysis, reducing airway inflammation in males. This work provides insight into sex-specific regulation of immunity, highlighting the interplay between hormones, metabolism, and immune function. The findings raise intriguing questions about how hormonal fluctuations affect immunity and how sex-specific metabolic pathways might be leveraged for targeted therapies in autoimmune diseases.
Authors
Nikita L. Mani, Samuel E. Weinberg
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The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway is a critical driver of type I interferon (IFN-I) and antitumor CD8+ T cell responses after radiotherapy (RT). In this issue of the JCI, two reports describe mechanisms that restrained STING signaling and abrogated antitumor immunity after RT. Wen, Wang, and colleagues discovered that IFN-I mediated the induction of YTHDF1, an RNA N6-methyladenosine–binding protein, in DCs after RT promoted cathepsin-mediated STING degradation. Zhang, Deng, Wu, and colleagues discovered that hemeoxygenase 1 (HO-1) was induced and proteolytically cleaved after RT to suppress cGAS cytoplasmic export as well as STING oligomerization at the ER. Blocking the STING-suppressive functions of YTHDF1 and HO-1, respectively, improved antitumor T cell immunity and tumor control after RT. Together, these studies support the development of clinical avenues to sustain STING signaling during RT, a standard treatment for approximately 50% of malignancies.
Authors
Michael C. Brown, Justin T. Low, Michelle L. Bowie, David M. Ashley
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The transmissible nature of prion diseases enables reproduction of neurodegeneration in small animal models that faithfully follows the disease process observed in the natural disease of animals and humans. This allows the temporal development of disease to be investigated and correlated with pathology in a complex brain environment. In this issue of the JCI, Makarava et al. describe a shift in microglia morphology from an active phagocytic phenotype to a passive association with neuronal cell bodies. Whether this morphological change reflects a supportive action of microglia in response to neuronal impairment or exhaustion of PrPSc-laden microglia remains to be determined. However, if microglial populations effectively contain PrPSc propagation early in the infection process, as the current study suggests, identifying ways to maintain or enhance the function of this cell population could be the key to prolonging patient survival.
Authors
Victoria A. Lawson
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Research Letter
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Abstract
Authors
Hong Wang, Maria Miranda, Eizo Marutani, Paul Lichtenegger, Gregory R. Wojtkiewicz, Fumito Ichinose, Vamsi K. Mootha
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Research Articles
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Abstract
Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.
Authors
Alexis N. Cattin-Roy, Kimberly G. Laffey, Luan B. Le, Adam G. Schrum, Habib Zaghouani
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The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergized with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor–derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress–targeting strategy for treating a broad range of cancers.
Authors
Ting-Yu Chang, Yan Yan, Zih-Yao Yu, Moeez Rathore, Nian-Zhe Lee, Hui-Ju Tseng, Li-Hsin Cheng, Wei-Jan Huang, Wei Zhang, Ernest R. Chan, Yulan Qing, Ming-Lun Kang, Rui Wang, Kelvin K. Tsai, John J. Pink, William E. Harte, Stanton L. Gerson, Sung-Bau Lee
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Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol, the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared with lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multiomic phenotyping demonstrated that adipocyte-specific Lpin1–/– mice had a metabolically unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1–mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.
Authors
Andrew LaPoint, Jason M. Singer, Daniel Ferguson, Trevor M. Shew, M. Katie Renkemeyer, Hector H. Palacios, Rachael L. Field, Sireesha Yerrathota, Roshan Kumari, Mahalakshmi Shankaran, Gordon I. Smith, Jun Yoshino, Mai He, Gary J. Patti, Marc K. Hellerstein, Samuel Klein, Jonathan R. Brestoff, E. Matthew Morris, Brian N. Finck, Andrew J. Lutkewitte
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Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II–mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33–deficient donor mice, we show that graft fibroblast–derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.
Authors
Jordan J.P. Warunek, Lu Fan, Xue Zhang, Sihua Wang, Steven M. Sanders, Tengfang Li, Lisa R. Mathews, Gaelen K. Dwyer, Michelle A. Wood-Trageser, Stephanie Traczek, Andrew Lesniak, Kassandra Baron, Hailey Spencer, Johnny Bou Saba, Emmanuel León Colón, Tracy Tabib, Robert Lafyatis, Mark A. Ross, Anthony J. Demetris, Simon C. Watkins, Steven A. Webber, Khodor I. Abou-Daya, Hēth R. Turnquist
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Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells’ survival during BTK inhibitor–induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of Forkhead box protein O1 (FoxO1) transcription factor, which induces expression of Rictor, an assembly protein for the mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knockout or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. The FoxO1/Rictor/pAktS473 axis represents an early nongenetic adaptation to B cell receptor (BCR) inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically and its inhibition induces CLL cells’ apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T cell factors (CD40L, IL-4, and IL-21).
Authors
Laura Ondrisova, Vaclav Seda, Krystof Hlavac, Petra Pavelkova, Eva Hoferkova, Giorgia Chiodin, Lenka Kostalova, Gabriela Mladonicka Pavlasova, Daniel Filip, Josef Vecera, Pedro Faria Zeni, Jan Oppelt, Zuzana Kahounova, Rachel Vichova, Karel Soucek, Anna Panovska, Karla Plevova, Sarka Pospisilova, Martin Simkovic, Filip Vrbacky, Daniel Lysak, Stacey M. Fernandes, Matthew S. Davids, Alba Maiques-Diaz, Stella Charalampopoulou, Jose I. Martin-Subero, Jennifer R. Brown, Michael Doubek, Francesco Forconi, Jiri Mayer, Marek Mraz
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The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including valosin containing protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T-expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking, respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing therapeutical targets for SFTPCI73T-associated interstitial lung disease.
Authors
Xiaofang Tang, Wei Wei, Yuqing Sun, Timothy E. Weaver, Ernesto S. Nakayasu, Geremy Clair, John M. Snowball, Cheng-Lun Na, Karen S. Apsley, Emily P. Martin, Darrell N. Kotton, Konstantinos-Dionysios Alysandratos, Jiuzhou Huo, Jeffery D. Molkentin, William A. Gower, Xinhua Lin, Jeffrey A. Whitsett
×Abstract
Metabolic dysfunction–associated steatotic hepatitis (MASH) is a chronic progressive liver disease that is highly prevalent worldwide. MASH is characterized by hepatic steatosis, inflammation, fibrosis, and liver damage, which eventually result in liver dysfunction due to cirrhosis or hepatocellular carcinoma. However, the cellular and molecular mechanisms underlying MASH progression remain largely unknown. Here, we found an increase of the Nr4a family of orphan nuclear receptor expression in intrahepatic T cells from mice with diet-induced MASH. Loss of Nr4a1 and Nr4a2 in T cell (dKO) ameliorated liver cell death and fibrosis, thereby mitigating liver dysfunction in MASH mice. dKO resulted in reduction of infiltrated macrophages and Th1/Th17 cells, whereas it led to a massive accumulation of Tregs in the liver of MASH mice. Combined single-cell RNA transcriptomic and TCR sequencing analysis revealed that intrahepatic dKO Tregs exhibited enhanced T cell immunoreceptor with Ig and ITIM domains (TIGIT) and IL-10 expression and were clonally expanded during MASH progression. Mechanistically, we found that dKO Tregs expressed high levels of basic leucine zipper ATF-like transcription factor (Batf), which promotes Treg cell proliferation and function upon TCR stimulation. Collectively, our findings not only provide an insight into the impact of intrahepatic Treg cells on MASH pathogenesis, but also suggest a therapeutic potential of targeting of the Nr4a family to treat the disease.
Authors
Daisuke Aki, Taeko Hayakawa, Tanakorn Srirat, Shigeyuki Shichino, Minako Ito, Shin-Ichiroh Saitoh, Setsuko Mise-Omata, Akihiko Yoshimura
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Female individuals have an increased prevalence of many Th17 cell–mediated diseases, including asthma. Androgen signaling decreases Th17 cell–mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell–mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared with female individuals, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined that females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and that AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. In patients with asthma, circulating Th17 cells from men had minimal reliance upon glutamine uptake compared to Th17 cells from women. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
Authors
Nowrin U. Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M. Wolf, Matthew Z. Madden, Shelby N. Kuehnle, Kaitlin E. McKernan, Erin Q. Jennings, Emily N. Arner, Darren R. Heintzman, Channing Chi, Ayaka Sugiura, Matthew T. Stier, Kelsey Voss, Xiang Ye, Kennedi Scales, Evan S. Krystofiak, Vivek D. Gandhi, Robert D. Guzy, Katherine N. Cahill, Anne I. Sperling, R. Stokes Peebles Jr., Jeffrey C. Rathmell, Dawn C. Newcomb
×Abstract
Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore an approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual–adeno-associated virus (dual-AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 protein in clinically relevant retinal models, including human retinal organoids and nonhuman primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.
Authors
Maryna V. Ivanchenko, Daniel M. Hathaway, Eric M. Mulhall, Kevin T.A. Booth, Mantian Wang, Cole W. Peters, Alex J. Klein, Xinlan Chen, Yaqiao Li, Bence György, David P. Corey
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Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on the mitochondrial outer membrane, which serve as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed; however, the checkpoint governing MAVS aggregation remains elusive. Here, we demonstrated that the palmitoylation of MAVS at cysteine 79 (C79), which is catalyzed mainly by the palmitoyl S-acyltransferase ZDHHC12, was essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, the systemic lupus erythematosus–associated mutation MAVS C79F was associated with defective palmitoylation, resulting in low type I interferon (IFN) production. Accordingly, Zdhhc12 deficiency apparently impaired RNA virus–induced type I IFN responses, and Zdhhc12-deficient mice were highly susceptible to lethal viral infection. These findings reveal a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.
Authors
Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui
×Abstract
Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted nonclassical functions of Ku70 in cellular processes. However, its function in immune homeostasis and antitumor immunity remains unknown. Here, we discovered a marked association between elevated Ku70 expression and unfavorable prognosis in lung adenocarcinoma, focusing specifically on increased Ku70 levels in tumor-infiltrated Tregs. Using a lung-colonizing tumor model in mice with Treg-specific Ku70 deficiency, we demonstrated that deletion of Ku70 in Tregs led to a stronger antitumor response and slower tumor growth due to impaired immune-suppressive capacity of Tregs. Furthermore, we confirmed that Ku70 played a critical role in sustaining the suppressive function of human Tregs. We found that Ku70 bound to forkhead box protein P3 (FOXP3) and occupied FOXP3-bound genomic sites to support its transcriptional activities. These findings not only unveil a nonhomologous end joining–independent (NHEJ-independent) role of Ku70 crucial for Treg-suppressive function, but also underscore the potential of targeting Ku70 as an effective strategy in cancer therapy, aiming to both restrain cancer cells and enhance pulmonary antitumor immunity.
Authors
Qianru Huang, Na Tian, Jianfeng Zhang, Shiyang Song, Hao Cheng, Xinnan Liu, Wenle Zhang, Youqiong Ye, Yanhua Du, Xueyu Dai, Rui Liang, Dan Li, Sheng-Ming Dai, Chuan Wang, Zhi Chen, Qianjun Zhou, Bin Li
×Abstract
Epidermal stem cells control homeostasis and regeneration of skin and hair. In the hair follicle (HF) bulge of mammals, populations of slow-cycling stem cells regenerate the HF during cyclical rounds of anagen (growth), catagen (regression), and telogen (quiescence). Multipotent epidermal cells are also present in the HF above the bulge area, contributing to the formation and maintenance of sebaceous gland and upper and middle portions of the HF. Here, we report that the transcription factor KROX20 is enriched in an epidermal stem cell population located in the upper/middle HF. Expression analyses and lineage tracing using inducible Krox20-CreERT showed that Krox20-lineage cells migrate out of this HF region and contribute to the formation of the bulge in the HF, serving as ancestors of bulge stem cells. In vivo depletion of these cells arrests HF morphogenesis. This study identifies a marker for an epidermal stem cell population that is indispensable for hair homeostasis.
Authors
Elnaz Ghotbi, Edem Tchegnon, Zhiguo Chen, Stephen Li, Tracey Shipman, Yong Wang, Jenny Raman, Yumeng Zhang, Renee M. McKay, Chung-Ping Liao, Lu Q. Le
×Abstract
Type I IFNs (IFN-Is) induced by radiotherapy (RT) are critical for its efficacy, while the mechanism by which tumor cells inhibit IFN-I production remains largely unsolved. By an unbiased CRISPR screen, we identified hemeoxygenase 1 (HO-1) as an RT-related regulator of IFN-I production. Mechanistically, the ER-anchored, full-length HO-1 disrupted stimulator of IFN genes (STING) polymerization and subsequent coat protein complex II–mediated (COPII-mediated) ER-Golgi transportation, leading to hampered activation of downstream signaling. This process was exacerbated by the upregulation of HO-1 expression under RT. Importantly, RT also induced HO-1 cleavage. Cleaved HO-1 underwent nuclear translocation, interacted with cyclic GMP-AMP synthase (cGAS), and inhibited its nuclear export upon irradiation, leading to suppressed 2′3′-cyclic GMP-AMP (cGAMP) production. Furthermore, we revealed that HO-1 inhibitors could enhance local and distant tumor control of RT in vivo. Clinically, higher HO-1 expression was associated with a poorer prognosis and earlier tumor relapse after RT in multiple types of patient tumors. Collectively, through comprehensive inhibition of the cGAS/STING pathway, HO-1 strongly inhibited RT-induced IFN-I production, and targeting HO-1 was shown to be a promising RT-sensitizing therapeutic strategy.
Authors
Chuqing Zhang, Zhenji Deng, Jiawei Wu, Cong Ding, Zhe Li, Zhimin Xu, Weipeng Chen, Kaibin Yang, Hanmiao Wei, Tingxiang He, Liufen Long, Jun Ma, Cheng Xu, Xiaoyu Liang
×Abstract
Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrates that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, a critical shift occurred in microglial activity during the late preclinical stage, transitioning from PrPSc uptake to establishing extensive neuron-microglia body-to-body cell contacts. This change was followed by a rapid accumulation of PrPSc in the brain. Microglia that enveloped neurons exhibited hypertrophic, cathepsin D–positive lysosomal compartments. However, most neurons undergoing envelopment were only partially encircled by microglia. Despite up to 40% of cortical neurons being partially enveloped at clinical stages, only a small percentage of envelopment proceeded to full engulfment. Partially enveloped neurons lacked apoptotic markers, but showed signs of functional decline. Neuronal envelopment was independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. This phenomenon of partial envelopment was consistently observed across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a phenomenon of partial envelopment of neurons by reactive microglia in the context of an actual neurodegenerative disease, not a disease model.
Authors
Natallia Makarava, Tarek Safadi, Olga Bocharova, Olga Mychko, Narayan P. Pandit, Kara Molesworth, Simone Baiardi, Li Zhang, Piero Parchi, Ilia V. Baskakov
×Abstract
The RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from patients with cancer, but not in other immune cells tested. Elevated YTHDF1 expression in DCs was associated with poor outcomes for patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) by increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through stimulator of IFN genes/type I IFN (STING/IFN-I) signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine that significantly improved the therapeutic effect of RT and radioimmunotherapy in a murine melanoma model. Our findings reveal a layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.
Authors
Chuangyu Wen, Liangliang Wang, András Piffkó, Dapeng Chen, Xianbin Yu, Katarzyna Zawieracz, Jason Bugno, Kaiting Yang, Emile Z. Naccasha, Fei Ji, Jiaai Wang, Xiaona Huang, Stephen Y. Luo, Lei Tan, Bin Shen, Cheng Luo, Megan E. McNerney, Steven J. Chmura, Ainhoa Arina, Sean Pitroda, Chuan He, Hua Laura Liang, Ralph R. Weichselbaum
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Abstract
Authors
Kristine Bousset, Stefano Donega, Najim Ameziane, Tabea Fleischhammer, Dhanya Ramachandran, Miriam Poley-Gil, Detlev Schindler, Ingrid M. van de Laar, Franco Pagani, Thilo Dörk
Abstract
BACKGROUND. Previous epidemiologic studies of autoimmune diseases in the United States (US) have included a limited number of diseases or used meta-analyses that rely on different data collection methods and analyses for each disease. METHODS. To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from six large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time. RESULTS. Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least one autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than one autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age. CONCLUSION. Thus, we provide, for the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age. FUNDING. Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.
Authors
Aaron H. Abend, Ingrid He, Neil Bahroos, Stratos Christianakis, Ashley B. Crew, Leanna M. Wise, Gloria P. Lipori, Xing He, Shawn N. Murphy, Christopher D. Herrick, Jagannadha Avasarala, Mark G. Weiner, Jacob S. Zelko, Erica Matute-Arcos, Mark Abajian, Philip R.O. Payne, Albert M. Lai, Heath A. Davis, Asher A. Hoberg, Chris E. Ortman, Amit D. Gode, Bradley W. Taylor, Kristen I. Osinski, Damian N. Di Florio, Noel R. Rose, Frederick W. Miller, George C. Tsokos, DeLisa Fairweather
Abstract
Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not Tlr9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severe group. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.
Authors
LK Metthew Lam, Nathan J. Klingensmith, Layal Sayegh, Emily Oatman, Joshua S. Jose, Christopher V. Cosgriff, Kaitlyn A. Eckart, John McGinnis, Piyush Ranjan, Matthew Lanza, Nadir Yehya, Nuala J. Meyer, Robert P. Dickson, Nilam S. Mangalmurti
Abstract
BACKGROUND. Partial protective immunity to schistosomiasis develops over time, following repeated praziquantel treatment. Moreover, animals develop protective immunity after repeated immunisation with irradiated cercariae. Here, we evaluated development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni (Sm) in healthy, Schistosoma-naïve participants using single-sex controlled human Sm infection. METHODS. Twenty-four participants were randomised double-blind (1:1) to either the reinfection group, which received three exposures (week 0,9,18) to 20 male cercariae or the infection control group, which received two mock exposures with water (week 0,9) prior to cercariae exposure (week 18). Participants were treated with praziquantel (or placebo) at week 8, 17 and 30. Attack rates after the final exposure (week 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events were collected for safety. RESULTS. Twenty-three participants completed follow-up. No protective efficacy was seen, given 82% (9/11) attack rate after the final exposure in the reinfection group and 92% (11/12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; p =0.5). Related adverse events were higher after the first infection (45%), compared to the second (27%) and third infection (28%). Severe acute schistosomiasis was observed after the first infections only (2/12 in reinfection group and 2/12 in infection control group). CONCLUSION. Repeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported with subsequent infections, but did not result in protection against reinfection. TRIAL REGISTRATION. ClinicalTrials.gov NCT05085470. FUNDING. ERC Starting grant (no. 101075876).
Authors
Jan Pieter R. Koopman, Emma L. Houlder, Jacqueline J. Janse, Olivia A.C. Lamers, Geert V.T. Roozen, Jeroen C. Sijtsma, Miriam Casacuberta-Partal, Stan T. Hilt, M.Y. Eileen C. van der Stoep, Inge M. van Amerongen-Westra, Eric A.T. Brienen, Linda J. Wammes, Lisette van Lieshout, Govert J. van Dam, Paul L.A.M. Corstjens, Angela van Diepen, Maria Yazdanbakhsh, Cornelis H. Hokke, Meta Roestenberg
Abstract
The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi's sarcoma-associated herpesvirus (KSHV) infection, a cause of Kaposi's sarcoma prevalent among the elderly without HIV infection, and cellular senescence remains enigmatic. This study uncovers a fascinating link between cellular senescence and enhanced KSHV infectivity in human endothelial cells. Through a comprehensive proteomic analysis, we identified caveolin-1 and CD109 as novel host factors significantly upregulated in senescent cells that promote KSHV infection. Remarkably, CRISPR-Cas9-mediated knockout of these factors reduced KSHV binding and entry, leading to decreased viral infectivity. Furthermore, surface plasmon resonance analysis and confocal microscopy revealed a direct interaction between KSHV virions and CD109 on the cell surface during entry, with recombinant CD109 protein exhibiting an intriguing ability to inhibit infection by blocking virion binding. These findings uncover a previously unrecognized role of cellular senescence in enhancing KSHV infection through upregulation of specific host factors and provide novel insights into the complex interplay between aging and viral pathogenesis.
Authors
Myung-Ju Lee, Jun-Hee Yeon, Jisu Lee, Yun Hee Kang, Beom Seok Park, Joo Hee Park, Sung-Ho Yun, Dagmar Wirth, Seung-Min Yoo, Changhoon Park, Shou-Jiang Gao, Myung-Shin Lee
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Substance Use Disorders
Series edited by Henry R. Kranzler
Substance use disorders are characterized by heavy, regular use of one or more psychoactive substances, such as alcohol, nicotine, opioids, cannabis, and stimulants, as well as the development of tolerance and loss of control over use, risk-taking behavior, and physiological dependence. Misuse of psychoactive substances constitutes a growing worldwide burden with broad-ranging health consequences. In this review series, curated by Dr. Henry R. Kranzler, reviews will provide detailed updates on studies of the genetics, biology, and evolving treatment of substance use disorders.
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Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)