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Top read articles in the last 30 days

This list is updated daily and reflects the last month of access data. Articles older than two years will not be shown.

  • Research
  • Review
Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade
Joy Hsu, … , David H. Raulet, Michele Ardolino
Joy Hsu, … , David H. Raulet, Michele Ardolino
Published October 1, 2018; First published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4654-4668. https://doi.org/10.1172/JCI99317.
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Categories: Research Article Immunology

Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

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Abstract

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.

Authors

Joy Hsu, Jonathan J. Hodgins, Malvika Marathe, Chris J. Nicolai, Marie-Claude Bourgeois-Daigneault, Troy N. Trevino, Camillia S. Azimi, Amit K. Scheer, Haley E. Randolph, Thornton W. Thompson, Lily Zhang, Alexandre Iannello, Nikhita Mathur, Karen E. Jardine, Georgia A. Kirn, John C. Bell, Michael W. McBurney, David H. Raulet, Michele Ardolino

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Total views: 11920


Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart
Xing Fu, … , Burns C. Blaxall, Jeffery D. Molkentin
Xing Fu, … , Burns C. Blaxall, Jeffery D. Molkentin
Published May 1, 2018; First published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):2127-2143. https://doi.org/10.1172/JCI98215.
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Categories: Research Article Cardiology

Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart

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Abstract

Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.

Authors

Xing Fu, Hadi Khalil, Onur Kanisicak, Justin G. Boyer, Ronald J. Vagnozzi, Bryan D. Maliken, Michelle A. Sargent, Vikram Prasad, Iñigo Valiente-Alandi, Burns C. Blaxall, Jeffery D. Molkentin

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Total views: 11677


Insulin resistance causes inflammation in adipose tissue
Mitsugu Shimobayashi, … , Ralph Peterli, Michael N. Hall
Mitsugu Shimobayashi, … , Ralph Peterli, Michael N. Hall
Published April 2, 2018; First published March 12, 2018
Citation Information: J Clin Invest. 2018;128(4):1538-1550. https://doi.org/10.1172/JCI96139.
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Categories: Research Article Inflammation Metabolism

Insulin resistance causes inflammation in adipose tissue

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Abstract

Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa.

Authors

Mitsugu Shimobayashi, Verena Albert, Bettina Woelnerhanssen, Irina C. Frei, Diana Weissenberger, Anne Christin Meyer-Gerspach, Nicolas Clement, Suzette Moes, Marco Colombi, Jerome A. Meier, Marta M. Swierczynska, Paul Jenö, Christoph Beglinger, Ralph Peterli, Michael N. Hall

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Total views: 5874


mTORC1 feedback to AKT modulates lysosomal biogenesis through MiT/TFE regulation
Kaushal Asrani, … , Michael Skaro, Tamara L. Lotan
Kaushal Asrani, … , Michael Skaro, Tamara L. Lotan
Published December 2, 2019; First published September 17, 2019
Citation Information: J Clin Invest. 2019;129(12):5584-5599. https://doi.org/10.1172/JCI128287.
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Categories: Research Article Metabolism Oncology

mTORC1 feedback to AKT modulates lysosomal biogenesis through MiT/TFE regulation

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Abstract

The microphthalmia family of transcription factors (MiT/TFEs) controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. However, the mechanisms by which cells with constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we found that epidermal Tsc1 deletion resulted in a phenotype characterized by wavy hair and curly whiskers, and was associated with increased EGFR and HER2 degradation. Unexpectedly, constitutive mTORC1 activation with Tsc1 loss increased lysosomal content via upregulated expression and activity of MiT/TFEs, whereas genetic deletion of Rheb or Rptor or prolonged pharmacologic mTORC1 inactivation had the reverse effect. This paradoxical increase in lysosomal biogenesis by mTORC1 was mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE downregulation. Thus, inhibiting hyperactive AKT signaling in the context of mTORC1 loss-of-function fully restored MiT/TFE expression and activity. These data suggest that signaling feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling, respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.

Authors

Kaushal Asrani, Sanjana Murali, Brandon Lam, Chan-Hyun Na, Pornima Phatak, Akshay Sood, Harsimar Kaur, Zoya Khan, Michaël Noë, Ravi K. Anchoori, C. Conover Talbot Jr., Barbara Smith, Michael Skaro, Tamara L. Lotan

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Total views: 4506


Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine
Matthew C. Madison, … , David B. Corry, Farrah Kheradmand
Matthew C. Madison, … , David B. Corry, Farrah Kheradmand
Published October 1, 2019; First published September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4290-4304. https://doi.org/10.1172/JCI128531.
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Categories: Research Article Immunology Inflammation

Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine

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Abstract

Electronic nicotine delivery systems (ENDS) or e-cigarettes have emerged as a popular recreational tool among adolescents and adults. Although the use of ENDS is often promoted as a safer alternative to conventional cigarettes, few comprehensive studies have assessed the long-term effects of vaporized nicotine and its associated solvents, propylene glycol (PG) and vegetable glycerin (VG). Here, we show that compared with smoke exposure, mice receiving ENDS vapor for 4 months failed to develop pulmonary inflammation or emphysema. However, ENDS exposure, independent of nicotine, altered lung lipid homeostasis in alveolar macrophages and epithelial cells. Comprehensive lipidomic and structural analyses of the lungs revealed aberrant phospholipids in alveolar macrophages and increased surfactant-associated phospholipids in the airway. In addition to ENDS-induced lipid deposition, chronic ENDS vapor exposure downregulated innate immunity against viral pathogens in resident macrophages. Moreover, independent of nicotine, ENDS-exposed mice infected with influenza demonstrated enhanced lung inflammation and tissue damage. Together, our findings reveal that chronic e-cigarette vapor aberrantly alters the physiology of lung epithelial cells and resident immune cells and promotes poor response to infectious challenge. Notably, alterations in lipid homeostasis and immune impairment are independent of nicotine, thereby warranting more extensive investigations of the vehicle solvents used in e-cigarettes.

Authors

Matthew C. Madison, Cameron T. Landers, Bon-Hee Gu, Cheng-Yen Chang, Hui-Ying Tung, Ran You, Monica J. Hong, Nima Baghaei, Li-Zhen Song, Paul Porter, Nagireddy Putluri, Ramiro Salas, Brian E. Gilbert, Ilya Levental, Matthew J. Campen, David B. Corry, Farrah Kheradmand

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Total views: 2227


Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury
Wenjing Sun, … , Juan Peng, Andrea Tedeschi
Wenjing Sun, … , Juan Peng, Andrea Tedeschi
Published December 3, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI130391.
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Categories: Research Article Neuroscience

Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury

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Abstract

Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.

Authors

Wenjing Sun, Molly J.E. Larson, Conrad M. Kiyoshi, Alexander J. Annett, William A. Stalker, Juan Peng, Andrea Tedeschi

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Total views: 2086


Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance
Dhanya K. Nambiar, … , Amato Giaccia, Quynh Thu Le
Dhanya K. Nambiar, … , Amato Giaccia, Quynh Thu Le
Published December 2, 2019; First published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5553-5567. https://doi.org/10.1172/JCI129025.
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Categories: Research Article Oncology

Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance

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Abstract

Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.

Authors

Dhanya K. Nambiar, Todd Aguilera, Hongbin Cao, Shirley Kwok, Christina Kong, Joshua Bloomstein, Zemin Wang, Vangipuram S. Rangan, Dadi Jiang, Rie von Eyben, Rachel Liang, Sonya Agarwal, A. Dimitrios Colevas, Alan Korman, Clint T. Allen, Ravindra Uppaluri, Albert C. Koong, Amato Giaccia, Quynh Thu Le

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Total views: 1879


Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue
Anying Song, … , Philipp E. Scherer, Qiong A. Wang
Anying Song, … , Philipp E. Scherer, Qiong A. Wang
Published November 25, 2019; First published October 1, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI129167.
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Categories: Research Article Metabolism

Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue

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Abstract

Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a new brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes.

Authors

Anying Song, Wenting Dai, Min Jee Jang, Leonard Medrano, Zhuo Li, Hu Zhao, Mengle Shao, Jiayi Tan, Aimin Li, Tinglu Ning, Marcia M. Miller, Brian Armstrong, Janice M. Huss, Yi Zhu, Yong Liu, Viviana Gradinaru, Xiwei Wu, Lei Jiang, Philipp E. Scherer, Qiong A. Wang

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Total views: 1823


FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury
Monica Chang-Panesso, … , Akio Kobayashi, Benjamin D. Humphreys
Monica Chang-Panesso, … , Akio Kobayashi, Benjamin D. Humphreys
Published December 2, 2019; First published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5501-5517. https://doi.org/10.1172/JCI125519.
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Categories: Research Article Nephrology Stem cells

FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury

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Abstract

The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury.

Authors

Monica Chang-Panesso, Farid F. Kadyrov, Matthew Lalli, Haojia Wu, Shiyo Ikeda, Eirini Kefaloyianni, Mai M. Abdelmageed, Andreas Herrlich, Akio Kobayashi, Benjamin D. Humphreys

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Total views: 1819


Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response
Mahnaz Sahraei, … , Carlos Fernández-Hernando, Yajaira Suárez
Mahnaz Sahraei, … , Carlos Fernández-Hernando, Yajaira Suárez
Published December 2, 2019; First published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5518-5536. https://doi.org/10.1172/JCI127125.
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Categories: Research Article Angiogenesis Immunology

Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response

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Abstract

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.

Authors

Mahnaz Sahraei, Balkrishna Chaube, Yuting Liu, Jonathan Sun, Alanna Kaplan, Nathan L. Price, Wen Ding, Stanley Oyaghire, Rolando García-Milian, Sameet Mehta, Yana K. Reshetnyak, Raman Bahal, Paolo Fiorina, Peter M. Glazer, David L. Rimm, Carlos Fernández-Hernando, Yajaira Suárez

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Total views: 1723

Show more results

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators
Charles N. Serhan, Bruce D. Levy
Charles N. Serhan, Bruce D. Levy
Published July 2, 2018; First published May 14, 2018
Citation Information: J Clin Invest. 2018;128(7):2657-2669. https://doi.org/10.1172/JCI97943.
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Category: Review Series

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

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Abstract

Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury. These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation. Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation. Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs. This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective. We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies.

Authors

Charles N. Serhan, Bruce D. Levy

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Total views: 5443


Mechanisms and functions of cellular senescence
Nicolás Herranz, Jesús Gil
Nicolás Herranz, Jesús Gil
Published April 2, 2018
Citation Information: J Clin Invest. 2018;128(4):1238-1246. https://doi.org/10.1172/JCI95148.
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Category: Review Series

Mechanisms and functions of cellular senescence

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Abstract

Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non–cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.

Authors

Nicolás Herranz, Jesús Gil

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Total views: 1496


The gut microbiome and metabolic syndrome
Kruttika Dabke, … , Gustaf Hendrick, Suzanne Devkota
Kruttika Dabke, … , Gustaf Hendrick, Suzanne Devkota
Published October 1, 2019
Citation Information: J Clin Invest. 2019;129(10):4050-4057. https://doi.org/10.1172/JCI129194.
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Category: Review Series

The gut microbiome and metabolic syndrome

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Abstract

The metabolic syndrome (MetS) is a constellation of risk factors that, if left untreated, will often progress to greater metabolic defects such as type 2 diabetes and nonalcoholic fatty liver disease. While these risk factors have been established for over 40 years, the definition of MetS warrants reconsideration in light of the substantial data that have emerged from studies of the gut microbiome. In this Review we present the existing recent literature that supports the gut microbiome’s potential influence on the various risk factors of MetS. The interplay of the intestinal microbiota with host metabolism has been shown to be mediated by a myriad of factors, including a defective gut barrier, bile acid metabolism, antibiotic use, and the pleiotropic effects of microbially produced metabolites. These data show that events that start in the gut, often in response to external cues such as diet and circadian disruption, have far-reaching effects beyond the gut.

Authors

Kruttika Dabke, Gustaf Hendrick, Suzanne Devkota

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Total views: 1297


Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome
C. Ronald Kahn, … , Guoxiao Wang, Kevin Y. Lee
C. Ronald Kahn, … , Guoxiao Wang, Kevin Y. Lee
Published October 1, 2019
Citation Information: J Clin Invest. 2019;129(10):3990-4000. https://doi.org/10.1172/JCI129187.
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Category: Review Series

Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome

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Abstract

Over the past decade, great progress has been made in understanding the complexity of adipose tissue biology and its role in metabolism. This includes new insights into the multiple layers of adipose tissue heterogeneity, not only differences between white and brown adipocytes, but also differences in white adipose tissue at the depot level and even heterogeneity of white adipocytes within a single depot. These inter- and intra-depot differences in adipocytes are developmentally programmed and contribute to the wide range of effects observed in disorders with fat excess (overweight/obesity) or fat loss (lipodystrophy). Recent studies also highlight the underappreciated dynamic nature of adipose tissue, including potential to undergo rapid turnover and dedifferentiation and as a source of stem cells. Finally, we explore the rapidly expanding field of adipose tissue as an endocrine organ, and how adipose tissue communicates with other tissues to regulate systemic metabolism both centrally and peripherally through secretion of adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, and miRNAs packaged in exosomes. Together these attributes and complexities create a robust, multidimensional signaling network that is central to metabolic homeostasis.

Authors

C. Ronald Kahn, Guoxiao Wang, Kevin Y. Lee

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Total views: 1249


Metabolically healthy obesity: facts and fantasies
Gordon I. Smith, … , Bettina Mittendorfer, Samuel Klein
Gordon I. Smith, … , Bettina Mittendorfer, Samuel Klein
Published October 1, 2019; First published September 16, 2019
Citation Information: J Clin Invest. 2019;129(10):3978-3989. https://doi.org/10.1172/JCI129186.
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Category: Review Series

Metabolically healthy obesity: facts and fantasies

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Abstract

Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered “metabolically healthy.” However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO — specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.

Authors

Gordon I. Smith, Bettina Mittendorfer, Samuel Klein

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Total views: 988


Killers 2.0: NK cell therapies at the forefront of cancer control
Jonathan J. Hodgins, … , Rebecca C. Auer, Michele Ardolino
Jonathan J. Hodgins, … , Rebecca C. Auer, Michele Ardolino
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(9):3499-3510. https://doi.org/10.1172/JCI129338.
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Category: Review

Killers 2.0: NK cell therapies at the forefront of cancer control

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Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes involved in the surveillance and elimination of cancer. As we have learned more and more about the mechanisms NK cells employ to recognize and eliminate tumor cells, and how, in turn, cancer evades NK cell responses, we have gained a clear appreciation that NK cells can be harnessed in cancer immunotherapy. Here, we review the evidence for NK cells’ critical role in combating transformed and malignant cells, and how cancer immunotherapies potentiate NK cell responses for therapeutic purposes. We highlight cutting-edge immunotherapeutic strategies in preclinical and clinical development such as adoptive NK cell transfer, chimeric antigen receptor–expressing NK cells (CAR-NKs), bispecific and trispecific killer cell engagers (BiKEs and TriKEs), checkpoint blockade, and oncolytic virotherapy. Further, we describe the challenges that NK cells face (e.g., postsurgical dysfunction) that must be overcome by these therapeutic modalities to achieve cancer clearance.

Authors

Jonathan J. Hodgins, Sarwat T. Khan, Maria M. Park, Rebecca C. Auer, Michele Ardolino

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Total views: 949


Contribution of adipogenesis to healthy adipose tissue expansion in obesity
Lavanya Vishvanath, Rana K. Gupta
Lavanya Vishvanath, Rana K. Gupta
Published October 1, 2019
Citation Information: J Clin Invest. 2019;129(10):4022-4031. https://doi.org/10.1172/JCI129191.
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Category: Review Series

Contribution of adipogenesis to healthy adipose tissue expansion in obesity

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Abstract

The manner in which white adipose tissue (WAT) expands and remodels directly impacts the risk of developing metabolic syndrome in obesity. Preferential accumulation of visceral WAT is associated with increased risk for insulin resistance, whereas subcutaneous WAT expansion is protective. Moreover, pathologic WAT remodeling, typically characterized by adipocyte hypertrophy, chronic inflammation, and fibrosis, is associated with insulin resistance. Healthy WAT expansion, observed in the “metabolically healthy” obese, is generally associated with the presence of smaller and more numerous adipocytes, along with lower degrees of inflammation and fibrosis. Here, we highlight recent human and rodent studies that support the notion that the ability to recruit new fat cells through adipogenesis is a critical determinant of healthy adipose tissue distribution and remodeling in obesity. Furthermore, we discuss recent advances in our understanding of the identity of tissue-resident progenitor populations in WAT made possible through single-cell RNA sequencing analysis. A better understanding of adipose stem cell biology and adipogenesis may lead to novel strategies to uncouple obesity from metabolic disease.

Authors

Lavanya Vishvanath, Rana K. Gupta

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Total views: 942


Targeting innate immunity for tuberculosis vaccination
Shabaana A. Khader, … , Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18
Shabaana A. Khader, … , Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(9):3482-3491. https://doi.org/10.1172/JCI128877.
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Category: Review

Targeting innate immunity for tuberculosis vaccination

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Abstract

Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.

Authors

Shabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18

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Total views: 822


Adipocyte and lipid metabolism in cancer drug resistance
Yihai Cao
Yihai Cao
Published August 1, 2019; First published July 2, 2019
Citation Information: J Clin Invest. 2019;129(8):3006-3017. https://doi.org/10.1172/JCI127201.
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Category: Review

Adipocyte and lipid metabolism in cancer drug resistance

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Abstract

Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells’ dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.

Authors

Yihai Cao

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Total views: 778


A review of current theories and treatments for phantom limb pain
Kassondra L. Collins, … , Robert S. Waters, Jack W. Tsao
Kassondra L. Collins, … , Robert S. Waters, Jack W. Tsao
Published June 1, 2018
Citation Information: J Clin Invest. 2018;128(6):2168-2176. https://doi.org/10.1172/JCI94003.
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Category: Review

A review of current theories and treatments for phantom limb pain

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Abstract

Following amputation, most amputees still report feeling the missing limb and often describe these feelings as excruciatingly painful. Phantom limb sensations (PLS) are useful while controlling a prosthesis; however, phantom limb pain (PLP) is a debilitating condition that drastically hinders quality of life. Although such experiences have been reported since the early 16th century, the etiology remains unknown. Debate continues regarding the roles of the central and peripheral nervous systems. Currently, the most posited mechanistic theories rely on neuronal network reorganization; however, greater consideration should be given to the role of the dorsal root ganglion within the peripheral nervous system. This Review provides an overview of the proposed mechanistic theories as well as an overview of various treatments for PLP.

Authors

Kassondra L. Collins, Hannah G. Russell, Patrick J. Schumacher, Katherine E. Robinson-Freeman, Ellen C. O’Conor, Kyla D. Gibney, Olivia Yambem, Robert W. Dykes, Robert S. Waters, Jack W. Tsao

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Total views: 760

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