ALBERT

Description: 〈p〉Publication date: 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 1〈/p〉 〈p〉Author(s): Jade D. Bailey, Marina Diotallevi, Thomas Nicol, Eileen McNeill, Andrew Shaw, Surawee Chuaiphichai, Ashley Hale, Anna Starr, Manasi Nandi, Elena Stylianou, Helen McShane, Simon Davis, Roman Fischer, Benedikt M. Kessler, James McCullagh, Keith M. Channon, Mark J. Crabtree〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH〈sub〉4〈/sub〉) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719307843-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 1〈/p〉 〈p〉Author(s): Marie-Kristin Raulf, Timo Johannssen, Svea Matthiesen, Konstantin Neumann, Severin Hachenberg, Sabine Mayer-Lambertz, Fridolin Steinbeis, Jan Hegermann, Peter H. Seeberger, Wolfgang Baumgärtner, Christina Strube, Jürgen Ruland, Bernd Lepenies〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Malaria represents a major cause of death from infectious disease. Hemozoin is a 〈em〉Plasmodium〈/em〉-derived product that contributes to progression of cerebral malaria. However, there is a gap of knowledge regarding how hemozoin is recognized by innate immunity. Myeloid C-type lectin receptors (CLRs) encompass a family of carbohydrate-binding receptors that act as pattern recognition receptors in innate immunity. In the present study, we identify the CLR CLEC12A as a receptor for hemozoin. Dendritic cell-T cell co-culture assays indicate that the CLEC12A/hemozoin interaction enhances CD8〈sup〉+〈/sup〉 T cell cross-priming. Using the 〈em〉Plasmodium berghei〈/em〉 Antwerpen-Kasapa (ANKA) mouse model of experimental cerebral malaria (ECM), we find that CLEC12A deficiency protects mice from ECM, illustrated by reduced ECM incidence and ameliorated clinical symptoms. In conclusion, we identify CLEC12A as an innate sensor of plasmodial hemozoin.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719307818-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 1〈/p〉 〈p〉Author(s): Xuezhou Hou, Guobao Chen, William Bracamonte-Baran, Hee Sun Choi, Nicola L. Diny, Jungeun Sung, David Hughes, Taejoon Won, Megan Kay Wood, Monica V. Talor, David Joel Hackam, Karin Klingel, Giovanni Davogustto, Heinrich Taegtmeyer, Isabelle Coppens, Jobert G. Barin, Daniela Čiháková〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Two types of monocytes, Ly6C〈sup〉hi〈/sup〉 and Ly6C〈sup〉lo〈/sup〉, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6C〈sup〉hi〈/sup〉 and Ly6C〈sup〉lo〈/sup〉 cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6C〈sup〉hi〈/sup〉 monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6C〈sup〉lo〈/sup〉 monocyte-to-macrophage differentiation. We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6C〈sup〉hi〈/sup〉 MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6C〈sup〉lo〈/sup〉 monocytes resume their differentiation into MHCII〈sup〉+〈/sup〉 macrophages. We propose that MHCII〈sup〉+〈/sup〉Ly6C〈sup〉lo〈/sup〉 MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930765X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Diletta Di Mitri, Michela Mirenda, Jelena Vasilevska, Arianna Calcinotto, Nicolas Delaleu, Ajinkya Revandkar, Veronica Gil, Gunther Boysen, Marco Losa, Simone Mosole, Emiliano Pasquini, Rocco D’Antuono, Michela Masetti, Elena Zagato, Giovanna Chiorino, Paola Ostano, Andrea Rinaldi, Letizia Gnetti, Mariona Graupera, Ana Raquel Martins Figueiredo Fonseca〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that 〈em〉Pten〈/em〉-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in 〈em〉Pten〈/em〉〈sup〉pc−/−〈/sup〉; 〈em〉Trp53〈/em〉〈sup〉pc−/−〈/sup〉 mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, 〈em〉PTEN〈/em〉-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of 〈em〉TNFR1〈/em〉. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309726-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): John D. Gagnon, Robin Kageyama, Hesham M. Shehata, Marlys S. Fassett, Darryl J. Mar, Eric J. Wigton, Kristina Johansson, Adam J. Litterman, Pamela Odorizzi, Dimitre Simeonov, Brian J. Laidlaw, Marisella Panduro, Sana Patel, Lukas T. Jeker, Margaret E. Feeney, Michael T. McManus, Alexander Marson, Mehrdad Matloubian, Shomyseh Sanjabi, K. Mark Ansel〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Coordinate control of T cell proliferation, survival, and differentiation are essential for host protection from pathogens and cancer. Long-lived memory cells, whose precursors are formed during the initial immunological insult, provide protection from future encounters, and their generation is the goal of many vaccination strategies. microRNAs (miRNAs) are key nodes in regulatory networks that shape effective T cell responses through the fine-tuning of thousands of genes. Here, using compound conditional mutant mice to eliminate miR-15/16 family miRNAs in T cells, we show that miR-15/16 restrict T cell cycle, survival, and memory T cell differentiation. High throughput sequencing of RNA isolated by cross-linking immunoprecipitation of AGO2 combined with gene expression analysis in miR-15/16-deficient T cells indicates that these effects are mediated through the direct inhibition of an extensive network of target genes within pathways critical to cell cycle, survival, and memory.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309684-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Joshua J. Gruber, Justin Chen, Benjamin Geller, Natalie Jäger, Andrew M. Lipchik, Guangwen Wang, Allison W. Kurian, James M. Ford, Michael P. Snyder〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Individuals with a single functional copy of the 〈em〉BRCA2〈/em〉 tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to 〈em〉BRCA2〈/em〉 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function (“BRCA2-crisis”), which may contribute to disease. Here, we establish an 〈em〉in vitro〈/em〉 model for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from 〈em〉BRCA2〈/em〉 carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis 〈em〉in vitro〈/em〉, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309611-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Adam J. Vogrin, Neil I. Bower, Menachem J. Gunzburg, Sally Roufail, Kazuhide S. Okuda, Scott Paterson, Stephen J. Headey, Steven A. Stacker, Benjamin M. Hogan, Marc G. Achen〈/p〉 〈div〉 〈h6〉Summary〈/h6〉 〈p〉Lymphatic vascular development establishes embryonic and adult tissue fluid balance and is integral in disease. In diverse vertebrate organs, lymphatic vessels display organotypic function and develop in an organ-specific manner. In all settings, developmental lymphangiogenesis is considered driven by vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3), whereas a role for VEGFR2 remains to be fully explored. Here, we define the zebrafish Vegf/Vegfr code in receptor binding studies. We find that while Vegfd directs craniofacial lymphangiogenesis, it binds Kdr (a VEGFR2 homolog) but surprisingly, unlike in mammals, does not bind Flt4 (VEGFR3). Epistatic analyses and characterization of a 〈em〉kdr〈/em〉 mutant confirm receptor-binding analyses, demonstrating that Kdr is indispensible for rostral craniofacial lymphangiogenesis, but not caudal trunk lymphangiogenesis, in which Flt4 is central. We further demonstrate an unexpected yet essential role for Kdr in inducing lymphatic endothelial cell fate. This work reveals evolutionary divergence in the Vegf/Vegfr code that uncovers spatially restricted mechanisms of developmental lymphangiogenesis.〈/p〉 〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309593-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Susan Lindtner, Rinaldo Catta-Preta, Hua Tian, Linda Su-Feher, James D. Price, Diane E. Dickel, Vanille Greiner, Shanni N. Silberberg, Gabriel L. McKinsey, Michael T. McManus, Len A. Pennacchio, Axel Visel, Alex S. Nord, John L.R. Rubenstein〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉DLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of 〈em〉Dlx1&2〈/em〉 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with 〈em〉in situ〈/em〉 hybridization (ISH), and 〈em〉in vivo〈/em〉 and 〈em〉in vitro〈/em〉 studies of regulatory element (RE) function. This revealed the DLX-organized gene regulatory network at genomic, cellular, and spatial levels in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to 〈em〉Dlx1&2〈/em〉 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930912X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Patrícia M. Silva, Charles Puerner, Agnese Seminara, Martine Bassilana, Robert A. Arkowitz〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉During symmetry breaking, the highly conserved Rho GTPase Cdc42 becomes stabilized at a defined site via an amplification process. However, little is known about how a new polarity site is established in an already asymmetric cell—a critical process in a changing environment. The human fungal pathogen 〈em〉Candida albicans〈/em〉 switches from budding to filamentous growth in response to external cues, a transition controlled by Cdc42. Here, we have used optogenetic manipulation of cell polarity to reset growth in asymmetric filamentous 〈em〉C. albicans〈/em〉 cells. We show that increasing the level of active Cdc42 on the plasma membrane results in disruption of the exocyst subunit Sec3 localization and a striking 〈em〉de novo〈/em〉 clustering of secretory vesicles. This new cluster of secretory vesicles is highly dynamic, moving by hops and jumps, until a new growth site is established. Our results reveal that secretory vesicle clustering can occur in the absence of directional growth.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309660-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Xiao Yu, Bo Li, Geng-Jen Jang, Shan Jiang, Daohong Jiang, Jyan-Chyun Jang, Shu-Hsing Wu, Libo Shan, Ping He〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Proper transcriptome reprogramming is critical for hosts to launch an effective defense response upon pathogen attack. How immune-related genes are regulated at the posttranscriptional level remains elusive. We demonstrate here that P-bodies, the non-membranous cytoplasmic ribonucleoprotein foci related to 5′-to-3′ mRNA decay, are dynamically modulated in plant immunity triggered by microbe-associated molecular patterns (MAMPs). The DCP1-DCP2 mRNA decapping complex, a hallmark of P-bodies, positively regulates plant MAMP-triggered responses and immunity against pathogenic bacteria. MAMP-activated MAP kinases directly phosphorylate DCP1 at the serine〈sup〉237〈/sup〉 residue, which further stimulates its interaction with XRN4, an exonuclease executing 5′-to-3′ degradation of decapped mRNA. Consequently, MAMP treatment potentiates DCP1-dependent mRNA decay on a specific group of MAMP-downregulated genes. Thus, the conserved 5′-to-3′ mRNA decay elicited by the MAMP-activated MAP kinase cascade is an integral part of plant immunity. This mechanism ensures a rapid posttranscriptional downregulation of certain immune-related genes that may otherwise negatively impact immunity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309581-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉