Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

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Abstract

Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control for food intake and energy expenditure. Here we reported that, contrary to females, male mice lacking circadian nuclear receptors REV-ERB alpha and beta in the tuberal hypothalamus (HDKO) gained excessive weight on an obesogenic high fat diet due to both decreased energy expenditure and increased food intake during the light phase. Moreover, rebound food intake after fasting was markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior was due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity was impaired in HDKO mice on an obesogenic diet in a diurnal manner. Thus, REV-ERBs play a crucial role in hypothalamic control of food intake and diurnal leptin sensitivity in diet-induced obesity.

Authors

Marine Adlanmerini, Hoang C. B. Nguyen, Brianna M. Krusen, Clare W. Teng, Caroline E. Geisler, Lindsey C. Peed, Bryce J. Carpenter, Matthew R. Hayes, Mitchell A. Lazar

Ventromedial hypothalamic primary cilia control energy and skeletal homeostasis

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Abstract

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH-primary cilia are not yet known. In this study, we identify VMH-primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88 KOSF-1) using steroidogenic factor 1-Cre (SF1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH-primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function, as well as associated with insulin and leptin resistance. The effect of bone density accrual was independent from obesity, as it was caused by the decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88 KOSF-1 and VMH-primary cilia knock-down mice. Overall, our current study identifies VMH-primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.

Authors

Ji Su Sun, Dong Joo Yang, Ann W. Kinyua, Seul Gi Yoon, Je Kyung Seong, Juwon Kim, Seok Jun Moon, Dong Min Shin, Yun-Hee Choi, Ki Woo Kim

Promoting the success of women and minority physician-scientists in academic medicine: a dean’s perspective

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Abstract

Dr. Nancy Brown, Dean of the Yale School of Medicine, shares her perspective on the challenges facing women and minority faculty members and trainees in academic medicine and provides a reflection on how leaders in academic medicine can promote diversity, equity, and inclusion to enhance their success.

Authors

Nancy J. Brown

COVID-19 and myeloid cells: complex interplay correlates with lung severity

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Abstract

COVID-19 spans and wide range of symptoms, sometimes with profound immune system involvement. How immune cell subsets change during the disease course and with disease severity needs further study. While myeloid cells have been shown to initiate and maintain responses to pneumonia and lung inflammation, often playing a role in resolution, their involvement with COVID-19 remains unknown. In this issue of the JCI, Sánchez-Cerrillo and Pedro-Landete et al. investigated dendritic cells and monocytes from blood and bronchial secretions of patients with varying COVID-19 severity and with healthy controls. The authors conclude that circulating monocytes and DCs migrate from the blood into the inflamed lungs. While sampling differences in sex, collection timing, bacteria/fungal infection, and corticosteroid treatment limit interpretation, we believe that reprograming monocyte or macrophages by targeting immunometabolism, epigenetics, or the cytokine milieu holds promise in resolving lung-inflammation associated with COVID-19.

Authors

Franco R. D'Alessio, Nicola M. Heller

Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing

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Abstract

BACKGROUND. Transcriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq guided method to diagnose individuals across a wide range of ages and clinical phenotypes. METHODS. One hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) clinical site from 2014-2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis. RESULTS. The transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts. CONCLUSION. For our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.

Authors

David R. Murdock, Hongzheng Dai, Lindsay C. Burrage, Jill A. Rosenfeld, Shamika Ketkar, Michaela F. Müller, Vicente A. Yépez, Julien Gagneur, Pengfei Liu, Shan Chen, Mahim Jain, Gladys Zapata, Carlos A. Bacino, Hsiao-Tuan Chao, Paolo Moretti, William J. Craigen, Neil A. Hanchard, Brendan Lee

Protein tyrosine phosphatase non-receptor type 2 controls colorectal cancer development

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Abstract

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC) as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. Particularly, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T-cells and increased PTPN2 levels negatively correlated with PD1, CTLA4, STAT1 and granzyme A. In vivo, T-cell and dendritic cell-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T-cells, as well as CD8+ T-cell infiltration and cytotoxicity into the tumor. In direct relevance to CRC treatment, T-cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced anti-tumor memory formation upon tumor re-challenge in vivo. Our data suggest a role for PTPN2 in suppressing anti-tumor immunity and promoting tumor development in CRC patients. Our in vivo results uncover PTPN2 as a key player in controlling immunogenicity of CRC, with the strong potential to be exploited to promote cancer immunotherapy.

Authors

Egle Katkeviciute, Larissa Hering, Ana Montalban-Arques, Philipp Busenhart, Marlene Schwarzfischer, Roberto Manzini, Javier Conde, Kirstin Atrott, Silvia Lang, Gerhard Rogler, Elisabeth Naschberger, Vera S. Schellerer, Michael Stürzl, Andreas Rickenbacher, Matthias Turina, Achim Weber, Sebastian Leibl, Gabriel E. Leventhal, Mitchell Levesque, Onur Boyman, Michael Scharl, Marianne R. Spalinger

Recent endemic coronavirus infection is associated with less severe COVID-19

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Abstract

Four different endemic coronaviruses (eCoVs) are etiologic agents for the seasonal “common cold,” and these eCoVs share extensive sequence homology with human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we show that individuals with as compared to without a relatively recent documented eCoV were tested at greater frequency for respiratory infections but had similar rate of SARS-CoV-2 acquisition. Importantly, the patients with a previously detected eCoV had less severe coronavirus disease-2019 (COVID-19) illness. Our observations suggest that pre-existing immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.

Authors

Manish Sagar, Katherine Reifler, Michael Rossi, Nancy S. Miller, Pranay Sinha, Laura White, Joseph P. Mizgerd

COVID-19 survival associates with the immunoglobulin response to the SARS-CoV-2 spike Receptor Binding Domain

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Abstract

BACKGROUND. Serological assays are of critical importance to investigate correlates of response and protection in COVID-19, to define previous exposure to SARS-CoV-2 in populations and to verify the development of an adaptive immune response in infected individuals. METHODS. We studied 509 confirmed COVID-19 patients from the San Raffaele Hospital of Milan and 480 pre-pandemic organ donor sera collected in 2010-2012. Using fluid-phase luciferase immune precipitation (LIPS) assays, we characterized IgG, IgM, IgA antibodies to the spike Receptor Binding Domain (RBD), S1+S2, nucleocapsid, and ORF6 to 10 of SARS-CoV-2, to the HCoV-OC43 and HCoV-HKU1 betacoronaviruses spike S2, and the H1N1Ca2009 flu virus hemagglutinin. Sequential samples at 1 and 3 months post-hospital discharge were also tested in 95 patients for SARS-CoV-2 RBD antibodies. RESULTS. Antibodies developed rapidly against multiple SARS-CoV-2 antigens in 95% of patients by 4 weeks post-symptoms onset and IgG to the RBD increased until the 3rd month of follow-up. We observed a major synchronous expansion of antibodies to the HCoV-OC43 and HCoV-HKU1 spike S2. A likely co-infection with influenza was neither linked to a more severe presentation of the disease nor to a worse outcome. Of the measured antibody responses positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival. CONCLUSIONS. The measurement of antibodies to selected epitopes of SARS-CoV-2 antigens can offer a more accurate assessment of the humoral response in patients and its impact on survival. The presence of partially cross-reactive antibodies with other betacoronoviruses is likely to impact on serological assay specificity and interpretation.

Authors

Massimiliano Secchi, Elena Bazzigaluppi, Cristina Brigatti, Ilaria Marzinotto, Cristina Tresoldi, Patrizia Rovere-Querini, Andrea Poli, Antonella Castagna, Gabriella Scarlatti, Alberto Zangrillo, Fabio Ciceri, Lorenzo Piemonti, Vito Lampasona

Endothelial C3a receptor mediates vascular inflammation and BBB permeability during aging

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Abstract

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer’s disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial-specific ablation of C3ar1. Using an in vitro model of the BBB, we identify intracellular Ca2+ as a downstream effector of C3a-C3aR signaling and a functional mediator of VE-cadherins junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation is also observed in a tau transgenic mouse model. Our studies suggest that heightened C3a-C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contribute to overall neuroinflammation in aging and neurodegenerative disease.

Authors

Nicholas E. Propson, Ethan R. Roy, Alexandra Litvinchuk, Jorg Köhl, Hui Zheng

Brain immune cells undergo cGAS-STING-dependent apoptosis during herpes simplex virus type 1 infection

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Abstract

Protection of the brain from viral infections involves the type I interferon (IFN-I) system, defects in which renders humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels leads to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we here show that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, while lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices, or mice treated with caspase inhibitor, exhibited lower viral load and improved outcome of infection. Collectively, we identify an activation-induced apoptosis program in brain immune cells which down-modulates local immune responses.

Authors

Line S. Reinert, Ahmad S. Rashidi, Diana N. Tran, Georgios Katzilieris-Petras, Astrid K. Hvidt, Mette Gohr, Stefanie Fruhwürth, Chiranjeevi Bodda, Martin K. Thomsen, Mikkel H. Vendelbo, Ahmad Raza Khan, Brian Hansen, Petra Bergström, Lotta Agholme, Trine H. Mogensen, Maria H. Christensen, Jens R. Nyengaard, Ganes C. Sen, Henrik Zetterberg, Georges M.G.M. Verjans, Soren R. Paluden