Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3β phosphorylationTang, Zhongshu; Arjunan, Pachiappan; Lee, Chunsik; Li, Yang; Kumar, Anil; Hou, Xu; Wang, Bin; Wardega, Piotr; Zhang, Fan; Dong, Lijin; Zhang, Yongqing; Zhang, Shi-Zhuang; Ding, Hao; Fariss, Robert N.; Becker, Kevin G.; Lennartsson, Johan; Nagai, Nobuo; Cao, Yihai; Li, Xuri
doi: 10.1084/jem.20091704pmid: 20231377
Platelet-derived growth factor CC (PDGF-CC) is the third member of the PDGF family discovered after more than two decades of studies on the original members of the family, PDGF-AA and PDGF-BB. The biological function of PDGF-CC remains largely to be explored. We report a novel finding that PDGF-CC is a potent neuroprotective factor that acts by modulating glycogen synthase kinase 3β (GSK3β) activity. In several different animal models of neuronal injury, such as axotomy-induced neuronal death, neurotoxin-induced neuronal injury, 6-hydroxydopamine–induced Parkinson’s dopaminergic neuronal death, and ischemia-induced stroke, PDGF-CC protein or gene delivery protected different types of neurons from apoptosis in both the retina and brain. On the other hand, loss-of-function assays using PDGF-C null mice, neutralizing antibody, or short hairpin RNA showed that PDGF-CC deficiency/inhibition exacerbated neuronal death in different neuronal tissues in vivo. Mechanistically, we revealed that the neuroprotective effect of PDGF-CC was achieved by regulating GSK3β phosphorylation and expression. Our data demonstrate that PDGF-CC is critically required for neuronal survival and may potentially be used to treat neurodegenerative diseases. Inhibition of the PDGF-CC–PDGF receptor pathway for different clinical purposes should be conducted with caution to preserve normal neuronal functions. Footnotes Abbreviations used: 6-OHDA 6-hydroxydopamine CSF cerebrospinal fluid EB Evan’s blue GSK3β glycogen synthase kinase 3β HUVSMC human umbilical vein smooth muscle cell INL/ONL inner/outer nuclear layer MAPK mitogen-activated protein kinase MCAO middle cerebral artery occlusion NMDA N -methyl-D-aspartic acid ONC optic nerve crush PDGF-CC platelet-derived growth factor CC PDGFR-α PDGF receptor α RGC retinal ganglion cell SN substantia nigra ST striatum TH tyrosine hydroxylase TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling Submitted: 5 August 2009 Accepted: 11 February 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditionsFletcher, Anne L.; Lukacs-Kornek, Veronika; Reynoso, Erika D.; Pinner, Sophie E.; Bellemare-Pelletier, Angelique; Curry, Mark S.; Collier, Ai-Ris; Boyd, Richard L.; Turley, Shannon J.
doi: 10.1084/jem.20092642pmid: 20308362
Lymph node stromal cells (LNSCs) can induce potent, antigen-specific T cell tolerance under steady-state conditions. Although expression of various peripheral tissue–restricted antigens (PTAs) and presentation to naive CD8 + T cells has been demonstrated, the stromal subsets responsible have not been identified. We report that fibroblastic reticular cells (FRCs), which reside in the T cell zone of the LN, ectopically express and directly present a model PTA to naive T cells, inducing their proliferation. However, we found that no single LNSC subset was responsible for PTA expression; rather, each subset had its own characteristic antigen display. Studies to date have concentrated on PTA presentation under steady-state conditions; however, because LNs are frequently inflammatory sites, we assessed whether inflammation altered stromal cell–T cell interactions. Strikingly, FRCs showed reduced stimulation of T cells after Toll-like receptor 3 ligation. We also characterize an LNSC subset expressing the highest levels of autoimmune regulator, which responds potently to bystander inflammation by up-regulating PTA expression. Collectively, these data show that diverse stromal cell types have evolved to constitutively express PTAs, and that exposure to viral products alters the interaction between T cells and LNSCs. Footnotes Abbreviations used: AFP α fetoprotein Aire autoimmune regulator BEC blood endothelial cell DN double negative ECM extracellular matrix eTAC extrathymic Aire -expressing cell FRC fibroblastic reticular cell iFABP intestinal fatty acid–binding protein LEC lymphatic endothelial cell LNSC LN stromal cell mTEC medullary thymic epithelial cell PLP proteolipid protein PTA peripheral tissue–restricted antigen QPCR quantitative PCR TLR Toll-like receptor tOVA truncated OVA Tyr tyrosinase Submitted: 10 December 2009 Accepted: 23 February 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Antagonism of the complement component C4 by flavivirus nonstructural protein NS1Avirutnan, Panisadee; Fuchs, Anja; Hauhart, Richard E.; Somnuke, Pawit; Youn, Soonjeon; Diamond, Michael S.; Atkinson, John P.
doi: 10.1084/jem.20092545pmid: 20308361
The complement system plays an essential protective role in the initial defense against many microorganisms. Flavivirus NS1 is a secreted nonstructural glycoprotein that accumulates in blood, is displayed on the surface of infected cells, and has been hypothesized to have immune evasion functions. Herein, we demonstrate that dengue virus (DENV), West Nile virus (WNV), and yellow fever virus (YFV) NS1 attenuate classical and lectin pathway activation by directly interacting with C4. Binding of NS1 to C4 reduced C4b deposition and C3 convertase (C4b2a) activity. Although NS1 bound C4b, it lacked intrinsic cofactor activity to degrade C4b, and did not block C3 convertase formation or accelerate decay of the C3 and C5 convertases. Instead, NS1 enhanced C4 cleavage by recruiting and activating the complement-specific protease C1s. By binding C1s and C4 in a complex, NS1 promotes efficient degradation of C4 to C4b. Through this mechanism, NS1 protects DENV from complement-dependent neutralization in solution. These studies define a novel immune evasion mechanism for restricting complement control of microbial infection. Footnotes Abbreviations used: Ab antibody BHK baby hamster kidney CHO Chinese hamster ovasry CP classical pathway DENV dengue virus DF dengue fever DHF/DSS dengue hemorrhagic fever/dengue shock syndrome E sheep erythrocytes EA Ab-sensitized E fH factor H GPS guinea pig serum HRP horseradish peroxidase MCP membrane cofactor protein MFI mean fluorescence intensity sCR1 soluble complement receptor 1 WNV West Nile virus YFV yellow fever virus Submitted: 25 November 2009 Accepted: 10 February 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Lymph node–resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentationCohen, Jarish N.; Guidi, Cynthia J.; Tewalt, Eric F.; Qiao, Hui; Rouhani, Sherin J.; Ruddell, Alanna; Farr, Andrew G.; Tung, Kenneth S.; Engelhard, Victor H.
doi: 10.1084/jem.20092465pmid: 20308365
Peripheral immune tolerance is generally thought to result from cross-presentation of tissue-derived proteins by quiescent tissue-resident dendritic cells to self-reactive T cells that have escaped thymic negative selection, leading to anergy or deletion. Recently, we and others have implicated the lymph node (LN) stroma in mediating CD8 T cell peripheral tolerance. We demonstrate that LN-resident lymphatic endothelial cells express multiple peripheral tissue antigens (PTAs) independent of the autoimmune regulator (Aire). They directly present an epitope derived from one of these, the melanocyte-specific protein tyrosinase, to tyrosinase-specific CD8 T cells, leading to their deletion. We also show that other LN stromal subpopulations express distinct PTAs by mechanisms that vary in their Aire dependence. These results establish lymphatic endothelial cells, and potentially other LN-resident cells, as systemic mediators of peripheral immune tolerance. Footnotes Abbreviations used: Aire autoimmune regulator FRC fibroblastic reticular cell LEC lymphatic endothelial cell mRNA messenger RNA mTEC medullary thymic epithelial cell PTA peripheral tissue antigen Submitted: 18 November 2009 Accepted: 22 February 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
The adaptor molecule CARD9 is essential for tuberculosis controlDorhoi, Anca; Desel, Christiane; Yeremeev, Vladimir; Pradl, Lydia; Brinkmann, Volker; Mollenkopf, Hans-Joachim; Hanke, Karin; Gross, Olaf; Ruland, Jürgen; Kaufmann, Stefan H.E.
doi: 10.1084/jem.20090067pmid: 20351059
The cross talk between host and pathogen starts with recognition of bacterial signatures through pattern recognition receptors (PRRs), which mobilize downstream signaling cascades. We investigated the role of the cytosolic adaptor caspase recruitment domain family, member 9 (CARD9) in tuberculosis. This adaptor was critical for full activation of innate immunity by converging signals downstream of multiple PRRs. Card9 −/− mice succumbed early after aerosol infection, with higher mycobacterial burden, pyogranulomatous pneumonia, accelerated granulocyte recruitment, and higher abundance of proinflammatory cytokines and granulocyte colony-stimulating factor (G-CSF) in serum and lung. Neutralization of G-CSF and neutrophil depletion significantly prolonged survival, indicating that an exacerbated systemic inflammatory disease triggered lethality of Card9 −/− mice. CARD9 deficiency had no apparent effect on T cell responses, but a marked impact on the hematopoietic compartment. Card9 −/− granulocytes failed to produce IL-10 after Mycobaterium tuberculosis infection, suggesting that an absent antiinflammatory feedback loop accounted for granulocyte-dominated pathology, uncontrolled bacterial replication, and, ultimately, death of infected Card9 −/− mice. Our data provide evidence that deregulated innate responses trigger excessive lung inflammation and demonstrate a pivotal role of CARD9 signaling in autonomous innate host defense against tuberculosis. Footnotes Abbreviations used: AEC alveolar epithelial cell AG arabinogalactan BMDC BM-derived DC BMDM BM-derived macrophage CARD9 caspase recruitment domain family, member 9 CLR C-type lectin receptor DTH delayed-type hypersensitivity G-CSF granulocyte colony-stimulating factor INH isoniazid KC keritinocyte-derived chenokine mAGP mycolyl-AG PG MAME mycolic acid methyl ester MPO myeloperoxidase MTB Mycobacterium tuberculosis NLRs NOD-like receptors PG peptidoglycan p.i. post infection PMN polymorphonuclear neutrophil PRR pattern recognition receptor RIF rifampicin TB tuberculosis TDM trehalose dimycolate TLR Toll-like receptor Submitted: 8 January 2009 Accepted: 18 February 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Arginine methylation of the B cell antigen receptor promotes differentiationInfantino, Simona; Benz, Beate; Waldmann, Tanja; Jung, Manfred; Schneider, Robert; Reth, Michael
doi: 10.1084/jem.20091303pmid: 20231378
Signals processed through the B cell antigen receptor (BCR) control both the proliferation and differentiation of B lymphocytes. How these different signaling modes are established at the BCR is poorly understood. We show that a conserved arginine in the tail sequence of the Igα subunit of the BCR is methylated by the protein arginine methyltransferase 1. This modification negatively regulates the calcium and PI-3 kinase pathways of the BCR while promoting signals leading to B cell differentiation. Thus, Igα arginine methylation can play an important role in specifying the outcome of BCR signaling. Footnotes Abbreviations used: GST glutathione S-transferase HA hemagglutinin ITAM immunoreceptor tyrosine-based activation motif NIP 4-hydroxy-5-iodo-3-nitrophenyl acetyl PI3K PI-3 kinase PLA proximity ligation assay PRMT protein arginine methyltransferase PTK protein tyrosine kinase siRNA small interfering RNA Submitted: 15 June 2009 Accepted: 11 February 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Metabolism and the leukemic stem cellAbdel-Wahab, Omar; Levine, Ross L.
doi: 10.1084/jem.20100523pmid: 20368582
Acute leukemias are clonal disorders of hematopoiesis wherein a leukemic stem cell (LSC) acquires mutations that confer the capacity for unlimited self-renewal, impaired hematopoietic differentiation, and enhanced proliferation to the leukemic clone. Many recent advances in understanding the biology of leukemia have come from studies defining specific genetic and epigenetic abnormalities in leukemic cells. Three recent articles, however, further our understanding of leukemia biology by elucidating specific abnormalities in metabolic pathways in leukemic hematopoiesis. These studies potentially converge on the concept that modulation of reactive oxygen species (ROS) abundance may influence the pathogenesis and treatment of acute myeloid leukemia (AML). Footnotes Submitted: 15 March 2010 Accepted: 18 March 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).