bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocyte gp130 Expression Is Critical for the Control of Toxoplasma Encephalitis
Authors: Drögemüller Katrin , Helmuth Ulrike , Brunn Anna , Sakowicz-Burkiewicz Monika , Gutmann David H. , Mueller Werner , Deckert Martina , Schlüter Dirk 
Published: April 2014

Abstract
Toxoplasma gondii infects astrocytes, neurons and microglia cells in the CNS and, after acute encephalitis, persists within neurons. Robust astrocyte activation is a hallmark of Toxoplasma encephalitis (TE); however, the in vivo function of astrocytes is largely unknown. To study their role in TE we generated C57BL/6 GFAP-Cre gp130fl/fl mice (where GFAP is glial fibrillary acid protein), which lack gp130, the signal-transducing receptor for IL-6 family cytokines, in their astrocytes. In the TE of wild-type mice, the gp130 ligands IL-6, IL-11, IL-27, LIF, oncostatin M, ciliary neurotrophic factor, B cell stimulating factor, and cardiotrophin-1 were up-regulated. In addition, GFAP+ astrocytes of gp130fl/fl control mice were activated, increased in number, and efficiently restricted inflammatory lesions and parasites, thereby contributing to survival from TE. In contrast, T. gondii- infected GFAP-Cre gp130fl/fl mice lost GFAP+ astrocytes in inflammatory lesions resulting in an inefficient containment of inflammatory lesions, impaired parasite control, and, ultimately, a lethal necrotizing TE. Production of IFN-γ and the IFN-γ-induced GTPase (IGTP), which mediate parasite control in astrocytes, was even increased in GFAP-Cre gp130fl/fl mice, indicating that instead of the direct antiparasitic effect the immunoregulatory function of GFAP-Cre gp130fl/fl astrocytes was disturbed. Correspondingly, in vitro infected GFAP-Cre gp130fl/fl astrocytes inhibited the growth of T. gondii efficiently after stimulation with IFN-γ, whereas neighboring noninfected and TNF-stimulated GFAP-Cre gp130fl/fl astrocytes became apoptotic. Collectively, these are the first experiments demonstrating a crucial function of astrocytes in CNS infection.
Double-Stranded RNA Induces an Antiviral Defense Status in Epidermal Keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-Mediated Differential Signaling
Authors: Kalali Behnam Naderi , Köllisch Gabriele , Mages Jörg , Müller Thomas , Bauer Stefan , Wagner Hermann , Ring Johannes , Lang Roland , Mempel Martin , Ollert Markus 
Published: April 2014

Abstract
Emerging evidence suggests an important role for human epidermal keratinocytes in innate immune mechanisms against bacterial and viral skin infections. The proinflammatory effect of viral infections can be mimicked by double-stranded RNA (dsRNA). Herein, we demonstrate that keratinocytes express all known dsRNA sensing receptors at a constitutive and inducible level, and that they use several downstream signaling pathways leading to a broad pattern of gene expression, not only proinflammatory and immune response genes under the control of NF-κB, but also genes under transcriptional control of IRF3. As a consequence, dsRNA, a stimulus for TLR3, protein kinase R (PKR), and the RNA helicases retinoic acid-inducible gene I (RIG-I) and MDA5, induces a status of antiviral defense in keratinocytes. Using inhibitors for the various dsRNA signaling pathways and specific small interfering RNA for TLR3, RIG-I, and MDA5, we demonstrated that in human keratinocytes, TLR3 seems to be necessary for NF-κB but not for IRF3 activation, whereas RIG-I and MDA5 are crucial for IRF3 activation. PKR is essential for the dsRNA response in both signaling pathways and thus represents the central antiviral receptor for dsRNA stimulation. Moreover, human keratinocytes up-regulate TLR7, the receptor for single-stranded RNA, in response to stimulation with dsRNA, which renders keratinocytes functionally responsive to the TLR7 agonist gardiquimod, a member of the imidazoquinoline antiviral immune response modifier family. Thus, in addition to building a physical barrier against infectious pathogens, keratinocytes are specially equipped with a full antiviral defense program that enables them to efficiently target viral infections of the skin.
Host-Derived Extracellular Nucleic Acids Enhance Innate Immune Responses, Induce Coagulation, and Prolong Survival upon Infection in Insects
Authors: Altincicek Boran , Stötzel Sabine , Wygrecka Malgorzata , Preissner Klaus T. , Vilcinskas Andreas 
Published: April 2014

Abstract
Extracellular nucleic acids play important roles in human immunity and hemostasis by inducing IFN production, entrapping pathogens in neutrophil extracellular traps, and providing procoagulant cofactor templates for induced contact activation during mammalian blood clotting. In this study, we investigated the functions of extracellular RNA and DNA in innate immunity and hemolymph coagulation in insects using the greater wax moth Galleria mellonella a reliable model host for many insect and human pathogens. We determined that coinjection of purified Galleria-derived nucleic acids with heat-killed bacteria synergistically increases systemic expression of antimicrobial peptides and leads to the depletion of immune-competent hemocytes indicating cellular immune stimulation. These activities were abolished when nucleic acids had been degraded by nucleic acid hydrolyzing enzymes prior to injection. Furthermore, we found that nucleic acids induce insect hemolymph coagulation in a similar way as LPS. Proteomic analyses revealed specific RNA-binding proteins in the hemolymph, including apolipoproteins, as potential mediators of the immune response and hemolymph clotting. Microscopic ex vivo analyses of Galleria hemolymph clotting reactions revealed that oenocytoids (5–10% of total hemocytes) represent a source of endogenously derived extracellular nucleic acids. Finally, using the entomopathogenic bacterium Photorhabdus luminescens as an infective agent and Galleria caterpillars as hosts, we demonstrated that injection of purified nucleic acids along with P. luminescens significantly prolongs survival of infected larvae. Our results lend some credit to our hypothesis that host-derived nucleic acids have independently been co-opted in innate immunity of both mammals and insects, but exert comparable roles in entrapping pathogens and enhancing innate immune responses.
Vaccination without Autoantigen Protects against Collagen II-Induced Arthritis via Immune Deviation and Regulatory T Cells
Authors: Kochetkova Irina , Trunkle Theresa , Callis Gayle , Pascual David W. 
Published: April 2014

Abstract
Anti-inflammation immunotherapy has been successfully applied for the treatment of autoimmune diseases. Mucosal vaccines against autoimmune disorders are beneficial by influencing the regulatory compartment of gut and systemic adaptive immune systems. A Salmonella vector expressing colonization factor Ag I (CFA/I), shown to behave as an anti-inflammatory vaccine, stimulates the production of CD4+CD25+ T cells and regulatory cytokines. In this work, we queried whether Salmonella-CFA/I can protect DBA/1 mice from collagen-induced arthritis. The incidence of arthritis and cartilage loss in vaccinated DBA/1 mice was remarkably lower when compared with unprotected mice. Clinical findings were accompanied by the suppression of inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-27. Vaccination evoked a multi-tier response consisting of IL-4 producing Th2 cells, an increased production of TGF-β by CD4+ T cells, and suppression of collagen II-specific CD4+ T cell proliferation. To assess the contribution of Salmonella-CFA/I-primed CD4+ T cells, adoptive transfer studies with total CD4+, CD4+CD25−, or CD4+CD25+ T cells were performed 15 days postchallenge. Mice receiving either subset showed reduced disease incidence and low clinical scores; however, mice receiving total CD4+ T cells showed delayed disease onset by 10 days with reduced clinical scores, reduced IL-17 and IL-27, but enhanced IL-4, IL-10, IL-13, and TGF-β. Inhibition of TGF-β or IL-4 compromised protective immunity. These data show that Salmonella-CFA/I vaccination of DBA/1 mice protects against collagen-induced arthritis by stimulating TGF-β- and IL-4-producing regulatory CD4+ T cells.
Human Airway Smooth Muscle Promotes Human Lung Mast Cell Survival, Proliferation, and Constitutive Activation: Cooperative Roles for CADM1, Stem Cell Factor, and IL-6
Authors: Hollins Fay , Kaur Davinder , Yang Weidong , Cruse Glenn , Saunders Ruth , Sutcliffe Amanda , Berger Patrick , Ito Akihiko , Brightling Christopher E. , Bradding Peter 
Published: April 2014

Abstract
The microlocalization of mast cells within specific tissue compartments is thought to be critical for the pathophysiology of many diverse diseases. This is particularly evident in asthma where they localize to the airway smooth muscle (ASM) bundles. Mast cells are recruited to the ASM by numerous chemoattractants and adhere through CADM1, but the functional consequences of this are unknown. In this study, we show that human ASM maintains human lung mast cell (HLMC) survival in vitro and induces rapid HLMC proliferation. This required cell-cell contact and occurred through a cooperative interaction between membrane-bound stem cell factor (SCF) expressed on ASM, soluble IL-6, and CADM1 expressed on HLMC. There was a physical interaction in HLMC between CADM1 and the SCF receptor (CD117), suggesting that CADM1-dependent adhesion facilitates the interaction of membrane-bound SCF with its receptor. HLMC-ASM coculture also enhanced constitutive HLMC degranulation, revealing a novel smooth muscle-driven allergen-independent mechanism of chronic mast cell activation. Targeting these interactions in asthma might offer a new strategy for the treatment of this common disease.
Galectin-3 Is a Negative Regulator of Lipopolysaccharide-Mediated Inflammation
Authors: Li Yubin , Komai-Koma Mousa , Gilchrist Derek S. , Hsu Daniel K. , Liu Fu-Tong , Springall Tabitha , Xu Damo 
Published: April 2014

Abstract
Galectin-3 is a β-galactoside-binding lectin that plays an important role in inflammatory diseases. It also interacts with the surface carbohydrates of many pathogens, including LPS. However, its role in infection is not fully understood. Data presented herein demonstrate for the first time that galectin-3 is a negative regulator of LPS-induced inflammation. Galectin-3 is constitutively produced by macrophages and directly binds to LPS. Galectin-3-deficient macrophages had markedly elevated LPS-induced signaling and inflammatory cytokine production compared with wild-type cells, which was specifically inhibited by the addition of recombinant galectin-3 protein. In contrast, blocking galectin-3 binding sites by using a neutralizing Ab or its ligand, β-lactose, enhanced LPS-induced inflammatory cytokine expression by wild-type macrophages. In vivo, mice lacking galectin-3 were more susceptible to LPS shock associated with excessive induction of inflammatory cytokines and NO production. However, these changes conferred greater resistance to Salmonella infection. Thus, galectin-3 is a previously unrecognized, naturally occurring, negative regulator of LPS function, which protects the host from endotoxin shock but, conversely, favors Salmonella survival.
The Human IL-17F/IL-17A Heterodimeric Cytokine Signals through the IL-17RA/IL-17RC Receptor Complex
Authors: Wright Jill F. , Bennett Frann , Li Bilian , Brooks Jonathan , Luxenberg Deborah P. , Whitters Matthew J. , Tomkinson Kathleen N. , Fitz Lori J. , Wolfman Neil M. , Collins Mary , Dunussi-Joannopoulos Kyri , Chatterjee-Kishore Moitreyee , Carreno Beatriz M. 
Published: April 2014

Abstract
IL-17A and IL-17F, produced by the Th17 CD4+ T cell lineage, have been linked to a variety of inflammatory and autoimmune conditions. We recently reported that activated human CD4+ T cells produce not only IL-17A and IL-17F homodimers but also an IL-17F/IL-17A heterodimeric cytokine. All three cytokines can induce chemokine secretion from bronchial epithelial cells, albeit with different potencies. In this study, we used small interfering RNA and Abs to IL-17RA and IL-17RC to demonstrate that heterodimeric IL-17F/IL-17A cytokine activity is dependent on the IL-17RA/IL-17RC receptor complex. Interestingly, surface plasmon resonance studies indicate that the three cytokines bind to IL-17RC with comparable affinities, whereas they bind to IL-17RA with different affinities. Thus, we evaluated the effect of the soluble receptors on cytokine activity and we find that soluble receptors exhibit preferential cytokine blockade. IL-17A activity is inhibited by IL-17RA, IL-17F is inhibited by IL-17RC, and a combination of soluble IL-17RA/IL-17RC receptors is required for inhibition of the IL-17F/IL-17A activity. Altogether, these results indicate that human IL-17F/IL-17A cytokine can bind and signal through the same receptor complex as human IL-17F and IL-17A. However, the distinct affinities of the receptor components for IL-17A, IL-17F, and IL-17F/IL-17A heterodimer can be exploited to differentially affect the activity of these cytokines.
Annexin-1 Mediates TNF-α-Stimulated Matrix Metalloproteinase Secretion from Rheumatoid Arthritis Synovial Fibroblasts
Authors: Tagoe Clement E. , Marjanovic Nada , Park Jean Y. , Chan Edwin S. , Abeles Aryeh M. , Attur Mukundan , Abramson Steven B. , Pillinger Michael H. 
Published: April 2014

Abstract
Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-α. TNF-α induced a biphasic secretion of annexin-1 from RA SF. Early (≤60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC50 ≈ 25 μM) and time- (8–24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-α-stimulated MMP-1 secretion. Erk, Jnk, and NF-κB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-κB inhibitors had no effect on annexin-1 secretion stimulated by TNF-α but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-α and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-κB, and stimulate MMP-1 secretion.
The 15-Lipoxygenase-Modified High Density Lipoproteins 3 Fail to Inhibit the TNF-α-Induced Inflammatory Response in Human Endothelial Cells
Authors: Pirillo Angela , Uboldi Patrizia , Bolego Chiara , Kuhn Hartmut , Catapano Alberico Luigi 
Published: April 2014

Abstract
Endothelial dysfunction represents one of the earliest events in vascular atherogenesis. Proinflammatory stimuli activate endothelial cells, resulting in an increased expression of adhesion molecules and chemoattractants that mediate leukocyte and monocyte adhesion, migration, and homing. High density lipoproteins (HDL) inhibit endothelial cell expression of adhesion molecules in response to proinflammatory stimuli. In the present work, we demonstrate that the modification of HDL3 (the major and the most antiatherogenic HDL subfraction) by 15-lipoxygenase (15-LO), an enzyme overexpressed in the atherosclerotic lesions, impairs the anti-inflammatory activity of this lipoprotein. The 15-LO-modified HDL3 failed to inhibit TNF-α-mediated mRNA and protein induction of adhesion molecules and MCP-1 in several models of human endothelial cells, and promoted inflammatory response by up-regulating the expression of such mediators of inflammation and by increasing monocyte adhesion to endothelial cells. Moreover, 15-LO-modified HDL3 were unable to contrast the formation of reactive oxygen species in cells incubated with TNF-α, and increased the reactive oxygen species content in unstimulated cells. Activation of NF-κB and AP-1 was mainly involved in the expression of adhesion molecules and MCP-1 induced by 15-LO-HDL3. Altogether, these results demonstrate that enzymatic modification induced by 15-LO impaired the protective role of HDL3, generating a dysfunctional lipoprotein endowed with proinflammatory characteristics.
CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function
Authors: Golovina Tatiana N. , Mikheeva Tatiana , Suhoski Megan M. , Aqui Nicole A. , Tai Victoria C. , Shan Xiaochuan , Liu Ronghua , Balcarcel R. Robert , Fisher Nancy , Levine Bruce L. , Carroll Richard G. , Warner Noel , Blazar Bruce R. , June Carl H. , Riley James L. 
Published: April 2014

Abstract
The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only CD28 costimulation in the presence of rapamycin consistently generated Tregs that consistently suppressed xenogeneic graft-vs-host disease in immunodeficient mice. Restimulation of Tregs after 8–12 days of culture with CD28 costimulation in the presence of rapamycin resulted in &gt;1000-fold expansion of Tregs in &lt;3 wk. Next, we determined whether other costimulatory pathways could augment the replicative potential of CD28-costimulated Tregs. We observed that while OX40 costimulation augmented the proliferative capacity of CD28-costimulated Tregs, Foxp3 expression and suppressive function were diminished. These studies indicate that the costimulatory requirements for expanding Tregs differ from those for T effector cells and, furthermore, they extend findings from mouse Tregs to demonstrate that human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function in vivo.
Innate Antifungal Immunity of Human Eosinophils Mediated by a β2 Integrin, CD11b
Authors: Yoon Juhan , Ponikau Jens U. , Lawrence Christopher B. , Kita Hirohito 
Published: April 2014

Abstract
Eosinophils produce and release various proinflammatory mediators and also show immunomodulatory and tissue remodeling functions; thus, eosinophils may be involved in the pathophysiology of asthma and other eosinophilic disorders as well as host defense. Several major questions still remain. For example, how do human eosinophils become activated in diseased tissues or at the site of an immune response? What types of host immunity might potentially involve eosinophils? Herein, we found that human eosinophils react vigorously to a common environmental fungus, Alternaria alternata, which is implicated in the development and/or exacerbation of human asthma. Eosinophils release their cytotoxic granule proteins, such as eosinophil-derived neurotoxin and major basic protein, into the extracellular milieu and onto the surface of fungal organisms and kill the fungus in a contact-dependent manner. Eosinophils use their versatile β2 integrin molecule, CD11b, to adhere to a major cell wall component, β-glucan, but eosinophils do not express other common fungal receptors, such as dectin-1 and lactosylceramide. The I-domain of CD11b is distinctively involved in the eosinophils’ interaction with β-glucan. Eosinophils do not react with another fungal cell wall component, chitin. Because human eosinophils respond to and kill certain fungal organisms, our findings identify a previously unrecognized innate immune function for eosinophils. This immune response by eosinophils may benefit the host, but, in turn, it may also play a role in the development and/or exacerbation of eosinophil-related allergic human diseases, such as asthma.
B Cell Depletion with Anti-CD79 mAbs Ameliorates Autoimmune Disease in MRL/lpr Mice
Authors: Li Yongmei , Chen Fangqi , Putt Mary , Koo Yumee K. , Madaio Michael , Cambier John C. , Cohen Philip L. , Eisenberg Robert A. 
Published: April 2014

Abstract
MRL/lpr mice develop a spontaneous systemic lupus erythematosus-like autoimmune syndrome due to a dysfunctional Fas receptor, with contributions from other less well-defined genetic loci. The removal of B cells by genetic manipulation not only prevents autoantibody formation, but it also results in substantially reduced T cell activation and kidney inflammation. To determine whether B cell depletion by administration of Abs is effective in lupus mice with an intact immune system and established disease, we screened several B cell-specific mAbs and found that a combination of anti-CD79α and anti-CD79β Abs was most effective at depleting B cells in vivo. Anti-CD79 therapy started at 4–5 mo of age in MRL/lpr mice significantly decreased B cells (B220+CD19+) in peripheral blood, bone marrow, and spleens. Treated mice also had a significant increase in the number of both double-negative T cells and naive CD4+ T cells, and a decreased relative abundance of CD4+ memory cells. Serum anti-chromatin IgG levels were significantly decreased compared with controls, whereas serum anti-dsDNA IgG, total IgG, or total IgM were unaffected. Overall, survival was improved with lower mean skin scores and significantly fewer focal inflammatory infiltrates in submandibular salivary glands and kidneys. Anti-CD79 mAbs show promise as a potential treatment for systemic lupus erythematosus and as a model for B cell depletion in vivo.
FOXO1 Regulates L-Selectin and a Network of Human T Cell Homing Molecules Downstream of Phosphatidylinositol 3-Kinase
Authors: Fabre Stéphanie , Carrette Florent , Chen Jing , Lang Valérie , Semichon Monique , Denoyelle Christine , Lazar Vladimir , Cagnard Nicolas , Dubart-Kupperschmitt Anne , Mangeney Marianne , Fruman David A. , Bismuth Georges 
Published: April 2014

Abstract
In T cells, the PI3K pathway promotes proliferation and survival induced by Ag or growth factors, in part by inactivating the FOXO transcription factor 1. We now report that FOXO1 controls the expression of L-selectin, an essential homing molecule, in human T lymphocytes. This control is already operational in unprimed T cells and involves a transcriptional regulation process that requires the FOXO1 DNA-binding domain. Using transcriptional profiling, we demonstrate that FOXO1 also increases transcripts of EDG1 and EDG6, two sphingosine-1-phosphate receptors that regulate lymphocyte trafficking. Additionally, FOXO1 binds the promoter of the cell quiescence and homing regulator Krüppel-like factor 2 and regulates its expression. Together, these results reveal a new function of FOXO1 in the immune system and suggest that PI3K controls a coordinated network of transcription factors regulating both cell quiescence and homing of human T lymphocytes.