Scientific Show Stopper: An essential role for YAP/TAZ in developmental and pathogenic angiogenesis
During angiogenesis, growth factors stimulate differentiation of endothelial cells and coordinate their sprouting, migration, and assembly into vessels. While the major ligands and receptors that regulate angiogenesis have been identified, the transcriptional factors that underpin these complex signaling processes are not well defined. This week in the <I>JCI</i>, a study led by Gou Young Koh at the Korea Advanced Institute of Science and Technology reveals that sprouting angiogenesis, migration, vascular barrier maturation, and endothelial cell metabolism require YAP/TAZ expression.
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JCI insight: Visualizing lymphatic vasculature using VIPAR, volume information-based histopathological analysis by 3D reconstruction and data extraction: http://insight.jci.org/articles/view/93424
3D reconstruction of wholemount immunostained human skin biopsy: blood vessels (ESAM1, white), lymphatic vessels [PDPN, red), PROX1 nuclei (green)].
On the cover of JCI Insight: Rapamycin reverses persistent lymphatic malformation
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Current treatments for lymphatic malformations focus mainly on management, reflecting the diagnostic and therapeutic challenges associated with these conditions. Recent clinical observations suggest that the mTOR inhibitor rapamycin may ameliorate lymphatic abnormalities in humans, but a lack of mechanistic insight has hindered efforts to develop treatm...ent strategies. Researchers in Donald McDonald’s lab at UCSF’s Cardiovascular Research Institute examined the effects of rapamycin in preventing and treating lymphatic malformation in a mouse model of inducible pulmonary lymphangiectasia, which is characterized by leaky and expanded lymphatic vasculature. In the model, systemic rapamycin treatment rapidly attenuated the long-lasting lymphangiectasia induced by transient overexpression of VEGF-C. While rapamycin reduced pathologic lymphatic expansion, it did not affect the structure of normal lymphatics. Moreover, rapamycin treatment also suppressed abnormal lymphatic sprouting and proliferation when delivered during a period of VEGF-C overexpression, suggesting that mTOR inhibition can both prevent and reverse lymphatic malformation.
The featured image shows the pathological expansion of lymphatic vasculature (LYVE-1, green) following 7 days of inducible VEGF-C overexpression. Simultaneous treatment with rapamycin over the 7-day period reduced lymphangiectasia without affecting normal lymphangiogenesis (not shown).
5-HT2C receptors contribute to metabolic side effects of atypical antipsychotics
Atypical antipsychotics target multiple monoaminergic receptors in the brain, but their therapeutic effect on psychiatric disorders is believed to result from combined blockade of serotonin 5-HT2A and dopamine D2 receptors. Despite their efficacy, several atypical antipsychotics have undesirable side effects that drive obesity and type 2 diabetes. Caleb Lord and colleagues investigated the mechan...isms underlying excessive weight gain linked to atypical antipsychotics in olanzapine-treated mice. Olanzapine treatment led to hyperphagia, impaired glucose tolerance, and reductions in physical activity and energy expenditure. These increases in feeding and weight gain were blunted in 5-HT2C receptor-deficient mice as well as mice co-treated with the 5-HT2C agonist lorcaserin. Co-treatment with lorcaserin also led to improvements in glucose homeostasis, suggesting that selective targeting of 5-HT2C receptors may ameliorate the metabolic effects of atypical antipsychotics.
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Prolyl hydroxylase 2 expression limits activated neutrophil lifespan and function
During the acute phase of inflammation, activated neutrophils are rapidly recruited to sites of infection, where they release cytokines that intensify the inflammatory response. Mechanisms that restrict the duration of neutrophil responses are important for limiting tissue damage that results from long-lasting inflammation. Pranvera Sadiku and coworkers examined the role of the prolyl hydroxylas...e PHD2, which targets HIFs for degradation, in regulating the survival and function of activated neutrophils. They found that myeloid-specific PHD2 deficiency enhanced neutrophil responses, leading to exaggerated inflammatory responses and lung injury in S. pneumonia-infected mice. The increased function and survival of PHD2-deficient neutrophils were driven by boosts in glycolytic metabolism. These findings identify PHD2 as a critical regulator of neutrophil-mediated inflammatory responses as well as neutrophil metabolism, suggesting that it may be an important target in the treatment of inflammatory disease.
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In JCI Insight: Sex-specific metabolic differences linked to glioma outcome
While sex is now recognized as an important factor in the clinical manifestation and outcome of many diseases, including several forms of cancer, the drivers of sex-dependent differences are not fully understood. Dr. Joseph Ippolito and colleagues performed a retrospective analysis of transcriptomic data in The Cancer Genome Atlas collected from patients with low-grade gliomas and determined that male...-specific overexpression of glycolytic genes associates with decreased survival. Conversely, increased expression of glycolytic genes and the presence of IDH mutation in females was linked to longer survival. Furthermore, evaluation of metabolite data from an independent cohort of grade 2 gliomas confirmed that overall survival was decreased in males with altered levels of glycolytic metabolites. This apparent synergy between sex and tumor metabolism has potential to be exploited to better define glioma patient prognosis.
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Insights into the role of autoreactive T cells in type I diabetes
Self-reactive T cells are key drivers of the autoimmune destruction of β cells that gives rise to type 1 diabetes (T1D). Pathogenic T cell responses to islet cell autoantigens precede diagnosis and symptom onset in the pancreata of individuals at high risk for T1D. Alberto Pugliese reviews the progress that recent advancements in T cell detection and phenotyping and expanded access to clinical pathology have co...ntributed to our understanding of this chronic autoimmune disease. Although patients exhibit considerable diversity in the onset and presentation of T1D, increasing evidence indicates that therapies targeting “neoepitopes,” the products of post-translational modification of native islet antigens, may hold promise in halting the progression of insulitis in at-risk individuals. Pugliese also highlights the need for better characterization of factors that trigger T cell-mediated autoimmunity as well as the pattern of β cell destruction that precedes T1D onset.
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In JCI Insight: Targeting CCR6 in inflammatory disease
The chemokine receptor CCR6 is expressed on the surface pathogenic immune cells, including those that secrete IL-17 and IL-22, and mediates the recruitment of these cells to sites of inflammation. CCR6-expressing cells have been implicated in a variety of inflammatory and autoimmune diseases; therefore, targeting this receptor has therapeutic potential. Remy Robert and colleagues developed transgenic mice that express hum...an CCR6 (hCCR6) in the native Ccr6 locus and a humanized, antagonistic antibody against hCCR6. Treatment of hCCR6-expressing mice with anti-hCCR6 markedly improved inflammation and disease-associated phenotypes in animals with imiquimod-induced psoriasis (see accompanying image) and experimental autoimmune encephalitis (EAE), supporting further exploration of targeting CCR6 for treatment of Th17-mediated diseases.
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NBEAL2 mutations impair neutrophil- and NK cell-mediated pathogen defense
Platelet abnormalities and bleeding tendency in gray platelet syndrome (GPS) are linked to mutations in the scaffolding protein neurobeachin-like 2 (NBEAL2). Some GPS patients also display increased susceptibility to infection, but the effects of NBEAL mutations on other cells of the hematopoetic cell lineage are unknown. John Sowerby and colleagues evaluated the phenotype of NBEAL2-deficient mice and o...bserved marked impairments in neutrophil and NK cell function. Neutrophils in NBEAL2-deficient mice lacked multiple granule subsets (see the accompanying image), which increased their susceptibility to S. aureus infection. Loss of NBEAL2 also compromised degranulation in NK cells, resulting in profound defects in antiviral immunity. Further investigation of NBEAL2’s contribution to immune function may reveal mechanisms and pathways underlying immunodeficiency in GPS and other disorders.
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EGFR signaling in sensory neurons contributes to pain processing
The therapeutic options for patients with chronic pain are limited, and many carry the risk of addiction and undesirable side effects. While several case reports describe pain relief in cancer patients undergoing treatment with EGFR-targeting agents, the analgesic properties of EGFR inhibition have not been evaluated. Loren Martin and colleagues found that epiregulin-mediated activation of EGFR enhanced nocicept...ion in mouse models of inflammatory and chronic pain. In contrast, inhibiting EGFR at the tyrosine kinase site reduced pain sensitivity in these models. Sensory neurons of the dorsal root ganglion expressed EGFR abundantly (see the accompanying image), and EGFR expression was increased in mouse models of chronic pain. Moreover, an analysis of 3 human cohorts linked the epiregulin/EGFR pathway to chronic pain. The identification of EGFR as a potential analgesic target may aid the development of improved therapies for managing chronic pain.
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In JCI Insight: Atypical T cell population develops in response to early pathogen exposure
The adaptive immune response is the culmination of an individuals’ exposure to different pathogens and antigens throughout their life. Chronic infection is associated with T cell exhaustion; however, the effect of early pathogen exposure is not well understood. Ann Moormann and colleagues analyzed CD4+ and CD8+ T cell populations in children from areas with different burdens of malaria,... schistosomiasis and Epstein-Barr virus. Samples were collected from children as toddlers and then again when they were school age. As toddlers, there was no notable difference in T cell populations based on pathogen burden; however, at the later collection, children living in a high pathogen exposure area developed an atypical population of CD8dim T cells with an innate-like profile, stunted proliferation, and impaired T cell receptor signaling. The CD8dim T cells identified in this study appear to represent a distinct population that should be further characterized.
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GATA4 haploinsufficiency in liver cancer impairs the hepatocyte differentiation program
Chromosome 8 (8p) deletion is the most common chromosomal structural loss in hepatocellular carcinoma (HCC), but the key genes responsible for tumor development resulting from 8p deletion are unknown. In an analysis of commonly-deleted 8p segments, Francis Enane, Wai Ho Shuen, and coworkers identified the master transcription factor GATA4 as a possible tumor-suppressor gene in HCC. In a m...ouse model, liver-specific Gata4 haploinsufficiency led to liver enlargement, proliferation of hepatocyte precursors, and impaired hepatocyte differentiation. Enrichment of precursor genes and suppression of hepatocyte differentiation genes in Gata4-haploinsufficient mice resembled gene expression patterns in human HCC. Moreover, HCC livers with intact 8p harbored mutations that disrupted GATA4’s interactions with coactivators, and restoring these interactions in HCC cells normalized the expression of precursor and hepatocyte gene programs. Together, these findings indicate that GATA4 loss-of-function is a critical driver of HCC transformation.
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On the cover of JCI Insight: CCR2+ myeloid cells support pancreatic islet development
Cells of the myeloid lineage provide critical support to organs during neonatal development. In adulthood, they enable tissue regeneration after injury. Although myeloid cells expressing the chemokine receptor CCR2 are present in the adult pancreas, whether they play a role in pancreatic development is unknown. A study led by Laura Crisa at the University of Washington reveals that CCR2+ mye...loid cells are enriched in the neonatal pancreatic epithelium and contribute to β cell proliferation in mice. The featured image visualizes CCR2+ cells (red), epithelial cells (green), and β cells (blue) in pancreatic sections from a neonatal mouse at postnatal day 1. Depletion of pancreatic CCR2+ cells profoundly blunted epithelial cell proliferation and led to dysfunctional islet phenotypes, impaired glucose homeostasis, and decreased body weight. Adoptive transfer of CCR2+ cells rescued these deficits. The findings presented in this study indicate a requirement for CCR2+ myeloid cells in pancreatic proliferation during perinatal development.
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Immune responses differentially involve TNF signaling in allergic airway inflammation
Allergic asthma is often regarded as a disease of eosinophilic airway inflammation, but over half of asthmatic patients display predominant neutrophilia. The heterogeneity in asthma might be related to the diversity of allergens and adjuvants and the innate immune responses that they activate. Gregory Whitehead and colleagues dissected the inflammatory pathways and immune responses evoked in... TLR ligand-sensitized and protease-sensitized airways. Mice sensitized by inhaling an allergen together with TLR ligands developed eosinophilia and neutrophils following subsequent allergen challenge, whereas protease-mediated sensitization predominantly evoked eosinophilic inflammation. TLR ligand-mediated sensitization induced TNF signaling in airway epithelial cells and was associated with the differentiation of Th2 cells, but not Th17 cells. TNF also acted during the challenge phase, promoting Th17 cell, eosinophil, and neutrophil recruitment to the airway in TLR ligand-sensitized, but not protease-sensitized, mice. These findings might help to explain the variable efficacy of TNF antagonists in clinical trials. Further, the observations lay the groundwork for investigating allergen-specific immune pathways and personalized therapies for allergic asthma.
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