Reunião dia 20/jul/15

– Data da reunião :20/07/2015

– Tema da apresentação: Apresentação de artigos referentes a morfologia, morfometria e quantificação de neutrófilos expostos à fumaça de cigarro.

– Arquivo da apresentação: http://1drv.ms/1fjJ3w6

– Artigos apresentados: http://1drv.ms/1Gzut9I

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NATURE COMMUNICATIONS | ARTICLE OPEN

Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1

Sabine Vettorazzi, Constantin Bode,  Lien Dejager,        Lucien Frappart,   Ekaterina Shelest, Carina Klaßen,Alpaslan Tasdogan,    Holger M. Reichardt,        Claude Libert,       Marion Schneider, Falk Weih,N. Henriette Uhlenhaut, Jean-Pierre David,               Markus Gräler,                Anna Kleiman       & Jan P. Tuckermann

AffiliationsContributionsCorresponding authors

Nature Communications 6, Article number: 7796 doi:10.1038/ncomms8796

Received 16 December 2014 Accepted 11 June 2015 Published 17 July 2015

Abstract

Abstract• Introduction• Results• Discussion• Methods• Additional information• References• Acknowledgements• Author information• Supplementary information

Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by glucocorticoids and pro-inflammatory stimuli via the glucocorticoid receptor in macrophages increases circulating sphingosine 1-phosphate levels, which proves essential for the inhibition of inflammation. Chemical or genetic inhibition of SphK1 abrogates the therapeutic effects of glucocorticoids. Inflammatory p38 MAPK- and mitogen- and stress-activated protein kinase 1 (MSK1)-dependent pathways cooperate with glucocorticoids to upregulate SphK1 expression. Our findings support a critical role for SphK1 induction in the suppression of lung inflammation by glucocorticoids, and therefore provide rationales for effective anti-inflammatory therapies.

 

PNAS

Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation

Susanne de Boor1, Philipp Knyphausen1, Nora Kuhlmann, Sarah Wroblowski, Julian Brenig, Lukas Scislowski, Linda Baldus, Hendrik Nolte, Marcus Krüger, and Michael Lammers2

Author Affiliations Edited by Alan R. Fersht, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom, and approved June 5, 2015 (received for review March 26, 2015)

Significance

The small GTPase Ran plays fundamental roles in cellular processes such as nucleo-cytoplasmic transport, mitotic spindle formation, and nuclear envelope assembly. Recently, Ran was found to be lysine acetylated, among others, in functionally important regions such as switch I and switch II. Using the genetic code expansion concept we show that lysine acetylation affects many important aspects of Ran function such as RCC1-catalyzed nucleotide exchange, intrinsic nucleotide hydrolysis, import/export complex formation, and Ran subcellular localization. Finally, we present evidence for a regulation of Ran acetylation by sirtuin deacetylases and lysine acetyltransferases.

Abstract

Ran is a small GTP-binding protein of the Ras superfamily regulating fundamental cellular processes: nucleo-cytoplasmic transport, nuclear envelope formation and mitotic spindle assembly. An intracellular Ran•GTP/Ran•GDP gradient created by the distinct subcellular localization of its regulators RCC1 and RanGAP mediates many of its cellular effects. Recent proteomic screens identified five Ran lysine acetylation sites in human and eleven sites in mouse/rat tissues. Some of these sites are located in functionally highly important regions such as switch I and switch II. Here, we show that lysine acetylation interferes with essential aspects of Ran function: nucleotide exchange and hydrolysis, subcellular Ran localization, GTP hydrolysis, and the interaction with import and export receptors. Deacetylation activity of certain sirtuins was detected for two Ran acetylation sites in vitro. Moreover, Ran was acetylated by CBP/p300 and Tip60 in vitro and on transferase overexpression in vivo. Overall, this study addresses many important challenges of the acetylome field, which will be discussed.

 

Immunology

Contribution of Dendritic cells to the autoimmune pathology of Systemic Lupus Erythematosus

Juan P. Mackern-Oberti1,2, Carolina Llanos3, Claudia A. Riedel4,5, Susan M. Bueno1,5 andAlexis M. Kalergis1,3,5,*

DOI: 10.1111/imm.12504 This article is protected by copyright. All rights reserved.

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies and complement activation lead to multisystem tissue damage. The contribution of the individual genetic composition has been extensively studied, and several susceptibility genes related to immune pathways that participate in SLE pathogenesis have been identified. It has been proposed that SLE takes place when susceptibility factors interact with environmental stimuli leading to a deregulated immune response. Experimental evidence suggests that such events are related to the failure of T and B cell suppression mediated by defects in cell signaling, immune tolerance and apoptotic mechanism promoting autoimmunity. In addition, it has been reported that dendritic cells (DCs) from SLE patients, which are crucial in the modulation of peripheral tolerance to self-antigens, show an increased ratio of activating/inhibitory receptors on their surfaces. This phenotype and an augmented expression of co-stimulatory molecules is thought to be critical for disease pathogenesis. Accordingly, tolerogenic DCs (tolDCs) can be a potential strategy for developing antigen-specific therapies to reduce detrimental inflammation without causing systemic immunosuppression. In this review article we discuss the most relevant data relative to the contribution of DCs to the triggering of SLE.