bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemokine-Like Receptor 1 Expression and Chemerin-Directed Chemotaxis Distinguish Plasmacytoid from Myeloid Dendritic Cells in Human Blood
Authors: Zabel Brian A. , Silverio Amanda M. , Butcher Eugene C. 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (pDCs) are versatile cells of the immune response, secreting type I IFNs and differentiating into potent immunogenic or tolerogenic APCs. pDCs can express adhesion and chemokine receptors for lymphoid tissues, but are also recruited by unknown mechanisms during tissue inflammation. We use a novel mAb specific for serpentine chemokine-like receptor 1 (CMKLR1) to evaluate its expression by circulating leukocytes in humans. We show that CMKLR1 is expressed by circulating pDCs in human blood, whereas myeloid DCs (mDCs) as well as lymphocytes, monocytes, neutrophils, and eosinophils are negative. We identify a major serum agonist activity for CMKLR1 as chemerin, a proteolytically activated attractant and the sole known ligand for CMKLR1, and we show that chemerin is activated during blood coagulation and attracts pDC but not mDC in ex vivo chemotaxis assays. We conclude that CMKLR1 expression and chemerin-mediated chemotaxis distinguish circulating pDCs from mDCs, providing a potential mechanism for their differential contribution to or regulation of immune responses at sites of bleeding or inflammatory protease activity.
IL-12 Protects against Coxsackievirus B3-Induced Myocarditis by Increasing IFN-γ and Macrophage and Neutrophil Populations in the Heart
Authors: Fairweather DeLisa , Frisancho-Kiss Sylvia , Yusung Susy A. , Barrett Masheka A. , Davis Sarah E. , Steele Ronelle A. , Gatewood Shannon J. L. , Rose Noel R. 
Published: April 2014

Abstract
Th1-type immune responses, mediated by IL-12-induced IFN-γ, are believed to exacerbate certain autoimmune diseases. We recently found that signaling via IL-12Rβ1 increases coxsackievirus B3 (CVB3)-induced myocarditis. In this study, we examined the role of IL-12 on the development of CVB3-induced myocarditis using mice deficient in IL-12p35 that lack IL-12p70. We found that IL-12 deficiency did not prevent myocarditis, but viral replication was significantly increased. Although there were no changes in the total percentage of inflammatory cells in IL-12-deficient hearts compared with wild-type BALB/c controls by FACS analysis, macrophage and neutrophil populations were decreased. This decrease corresponded to reduced TNF-α and IFN-γ levels in the heart, suggesting that macrophage and/or neutrophil populations may be a primary source of TNF-α and IFN-γ during acute CVB3 myocarditis. Increased viral replication in IL-12-deficient mice was not mediated by reduced TNFRp55 signaling, because viral replication was unaltered in TNFRp55-deficient mice. However, STAT4 or IFN-γ deficiency resulted in significantly increased viral replication and significantly reduced TNF-α and IFN-γ levels in the heart, similar to IL-12 deficiency, indicating that the IL-12/STAT4 pathway of IFN-γ production is important in limiting CVB3 replication. Furthermore, STAT4 or IFN-γ deficiency also increased chronic CVB3 myocarditis, indicating that therapeutic strategies aimed at reducing Th1-mediated autoimmune diseases may exacerbate common viral infections such as CVB3 and increase chronic inflammatory heart disease.
Cutting Edge: NF-κB-Activating Kinase-Associated Protein 1 Participates in TLR3/Toll-IL-1 Homology Domain-Containing Adapter Molecule-1-Mediated IFN Regulatory Factor 3 Activation
Authors: Sasai Miwa , Oshiumi Hiroyuki , Matsumoto Misako , Inoue Norimitsu , Fujita Fumitaka , Nakanishi Makoto , Seya Tsukasa 
Published: April 2014

Abstract
TLRs signal the presence of microbial patterns and activate transcription factors. In TLR3 and TLR4, the adapter Toll-IL-1R homology domain-containing adapter molecule (TICAM-1) (also called Toll/IL-1R domain-containing adapter inducing IFN-β (TRIF)) mediates IFN regulatory factor 3 (IRF3) phosphorylation followed by IFN-β production. The regulatory subunit TNFR-associated factor family member-associated NF-κB activator (TANK) couples with the kinase complex IκB kinase-related kinase ε/NF-κB-activating kinase (NAK) (TANK-binding kinase 1 (TBK1)) that involveTICAM-1-dependent IFN-β induction. There are several TANK-homologous proteins. We tested whether TICAM-1 binds and coprecipitates with TANK or its family proteins. The results are: 1) the TANK family protein NAK-associated protein 1 (NAP1), but not TANK, coprecipitates withTICAM-1; 2) NAP1 overexpression markedly enhances TBK1-mediated IFN-β promoter activation; 3) a dominant-negative form, NAP (158–270), suppresses IRF3 activation in response to poly(I:C) or LPS; 4) RNA interference targeting of the NAP1 message results in a failure of poly(I:C)-mediated IRF3 polymerization and IFN-β production. Thus, NAP1 is the kinase subunit responsible for TLR3/4-mediated IFN-β induction in the TICAM-1 pathway.
Suppressive Effect of 1α,25-Dihydroxyvitamin D3 on Type I IFN-Mediated Monocyte Differentiation into Dendritic Cells: Impairment of Functional Activities and Chemotaxis
Authors: Gauzzi Maria Cristina , Purificato Cristina , Donato Karim , Jin Yixin , Wang Ling , Daniel Kenn C. , Maghazachi Azzam A. , Belardelli Filippo , Adorini Luciano , Gessani Sandra 
Published: April 2014

AbstractDendritic cells (DCs) generated by a single-step exposure of human monocytes to type I IFN and GM-CSF (IFN-DCs) are endowed with potent immunostimulatory activities and a distinctive migratory response to specific chemokines. In this study, we evaluated the effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D3, on the DC differentiation/activation induced by type I IFN. We found that 1,25(OH)2D3 prevented the generation of IFN-DCs when added to freshly isolated monocytes, and was capable of redirecting already differentiated IFN-DCs toward a more immature stage, as revealed by their immunophenotype, reduced allostimulatory activity, and impaired LPS-induced production of Th1-polarizing cytokines. Control and 1,25(OH)2D3-treated IFN-DCs exhibited a similar expression of vitamin D receptor, as well as comparable cell death rates. Furthermore, the chemotactic response of IFN-DCs to CCL4 and CCL19 was markedly reduced or completely abrogated by 1,25(OH)2D3. Despite these changes in the IFN-DC migratory behavior, the expression of CCR5 and CCR7 and the calcium fluxes triggered by CCL4 and CCL19 were not affected. These findings indicate that, in this innovative single-step DC generation model from monocytes, the suppressive effect of 1,25(OH)2D3 is associated with a potent impairment of DC migration in response to inflammatory and lymph node-homing chemokines, thus unraveling a novel mechanism involved in 1,25(OH)2D3-mediated immunomodulation.
Cutting Edge: Localization of Linker for Activation of T Cells to Lipid Rafts Is Not Essential in T Cell Activation and Development
Authors: Zhu Minghua , Shen Shudan , Liu Yan , Granillo Olivia , Zhang Weiguo 
Published: April 2014

Abstract
It has been proposed that upon T cell activation, linker for activation of T cells (LAT), a transmembrane adaptor protein localized to lipid rafts, orchestrates formation of multiprotein complexes and activates signaling cascades in lipid rafts. However, whether lipid rafts really exist or function remains controversial. To address the importance of lipid rafts in LAT function, we generated a fusion protein to target LAT to nonraft fractions using the transmembrane domain from a nonraft protein, linker for activation of X cells (LAX). Surprisingly, this fusion protein functioned well in TCR signaling. It restored MAPK activation, calcium flux, and NFAT activation in LAT-deficient cells. To further study the function of this fusion protein in vivo, we generated transgenic mice that express this protein. Analysis of these mice indicated that it was fully capable of replacing LAT in thymocyte development and T cell function. Our results demonstrate that LAT localization to lipid rafts is not essential during normal T cell activation and development.
The Functional and Structural Properties of MD-2 Required for Lipopolysaccharide Binding Are Absent in MD-1
Authors: Tsuneyoshi Naoko , Fukudome Kenji , Kohara Jun , Tomimasu Rika , Gauchat Jean-Francois , Nakatake Hiroshi , Kimoto Masao 
Published: April 2014

Abstract
MD-1 and MD-2 are secretory glycoproteins that exist on the cell surface in complexes with transmembrane proteins. MD-1 is anchored by radioprotective 105 (RP105), and MD-2 is associated with TLR4. In vivo studies revealed that MD-1 and MD-2 have roles in responses to LPS. Although the direct binding function of MD-2 to LPS has been observed, the physiological function of MD-1 remains unknown. In this study, we compared the LPS-binding functions of MD-1 and MD-2. LPS binding to cell surface complexes was detected for cells transfected with TLR4/MD-2. In contrast, binding was not observed for RP105/MD-1-transfected cells. When rMD-2 protein was expressed in Escherichia coli, it was purified in complexes containing LPS. In contrast, preparations of MD-1 did not contain LPS. When rMD-2 protein was prepared in a mutant strain lacking the lpxM gene, LPS binding disappeared. Therefore, the secondary myristoyl chain attached to the (R)-3-hydroxymyristoyl chain added by LpxM is required for LPS recognition by MD-2, under these conditions. An amphipathic cluster composed of basic and hydrophobic residues in MD-2 has been suggested to be the LPS-binding site. We specifically focused on two Phe residues (119 and 121), which can associate with fatty acids. A mutation at Phe191 or Phe121 strongly reduced binding activity, and a double mutation at these residues prevented any binding from occurring. The Phe residues are present in MD-2 and absent in MD-1. Therefore, the LPS recognition mechanism by RP105/MD-1 is distinct from that of TLR4/MD-2.
Mast Cells Acquire Monocyte-Specific Gene Expression and Monocyte-Like Morphology by Overproduction of PU.1
Authors: Ito Tomonobu , Nishiyama Chiharu , Nishiyama Makoto , Matsuda Hironori , Maeda Keiko , Akizawa Yushiro , Tsuboi Ryoji , Okumura Ko , Ogawa Hideoki 
Published: April 2014

Abstract
PU.1 is a myeloid- and lymphoid-specific transcription factor that belongs to the Ets family. Recently, we found that overproduction of PU.1 in mouse bone marrow-derived hemopoietic progenitor cells induced monocyte-specific gene expression and caused their monocyte-like morphological change. In the present study, PU.1 was overproduced by using retrovirus expression system in differentiated bone marrow-derived mast cells. By overexpression of PU.1, cell surface expression of MHC class II, CD11b, CD11c, and F4/80 was induced, accompanied by reduced expression of c-kit, a mast cell-specific marker. Morphology of PU.1-transfected cells was altered toward monocyte-like one. PU.1-overproducing cells acquired T cell stimulatory ability and showed an increase in response to LPS stimulation, while response through FcεRI was markedly reduced by overproduction of PU.1. These results suggest that the differentiated mast cells still have potential to display monocytic features. When PU.1 was overproduced in a different type of mast cell, peritoneal mast cells, similar monocyte-like morphological change, and the expression of CD11b and F4/80 were induced. However, surface level of CD11c and MHC class II was not affected. These results indicate that the potential capacity to exhibit monocytic features is different between both the mast cells.
Inhibition of Human Neutrophil IL-8 Production by Hydrogen Peroxide and Dysregulation in Chronic Granulomatous Disease
Authors: Lekstrom-Himes Julie A. , Kuhns Douglas B. , Alvord W. Gregory , Gallin John I. 
Published: April 2014

Abstract
The innate immune response to bacterial infections includes neutrophil chemotaxis and activation, but regulation of inflammation is less well understood. Formyl peptides, byproducts of bacterial metabolism as well as mitochondrial protein biosynthesis, induce neutrophil chemotaxis, the generation of reactive oxygen intermediates (ROI), and the production of the neutrophil chemoattractant, IL-8. Patients with chronic granulomatous disease (CGD) exhibit deficient generation of ROI and hydrogen peroxide and susceptibility to bacterial and fungal pathogens, with associated dysregulated inflammation and widespread granuloma formation. We show in this study that in CGD cells, fMLF induces a 2- to 4-fold increase in IL-8 production and a sustained IL-8 mRNA response compared with normal neutrophils. Moreover, normal neutrophils treated with catalase (H2O2 scavenger) or diphenyleneiodonium chloride (NADPH oxidase inhibitor) exhibit IL-8 responses comparable to those of CGD neutrophils. Addition of hydrogen peroxide or an H2O2-generating system suppresses the sustained IL-8 mRNA and increased protein production observed in CGD neutrophils. These results indicate that effectors downstream of the activation of NADPH oxidase negatively regulate IL-8 mRNA in normal neutrophils, and their absence in CGD cells results in prolonged IL-8 mRNA elevation and enhanced IL-8 levels. ROI may play a critical role in regulating inflammation through this mechanism.
Role of L-Ficolin/Mannose-Binding Lectin-Associated Serine Protease Complexes in the Opsonophagocytosis of Type III Group B Streptococci
Authors: Aoyagi Youko , Adderson Elisabeth E. , Min Jin G. , Matsushita Misao , Fujita Teizo , Takahashi Shinji , Okuwaki Yoshiyuki , Bohnsack John F. 
Published: April 2014

Abstract
Serotype III group B streptococci (GBS) are a common cause of neonatal sepsis and meningitis. Although deficiency in maternal capsular polysaccharide (CPS)-specific IgG correlates with susceptibility of neonates to the GBS infection, serum deficient in CPS-specific IgG mediates significant opsonophagocytosis. This IgG-independent opsonophagocytosis requires activation of the complement pathway, a process requiring the presence of both Ca2+ and Mg2+, and is significantly reduced by chelating Ca2+ with EGTA. In these studies, we defined a role of L-ficolin/mannose-binding lectin-associated serine protease (MASP) complexes in Ca2+-dependent, Ab-independent opsonophagocytosis of serotype III GBS. Incubation of GBS with affinity-purified L-ficolin/MASP complexes and C1q-depleted serum deficient in CPS-specific Ab supported opsonophagocytic killing, and this killing was inhibited by fluid-phase N-acetylglucosamine, the ligand for L-ficolin. Binding of L-ficolin was proportional to the CPS content of individual strains, and opsonophagocytic killing and C4 activation were inhibited by fluid-phase CPS, suggesting that L-ficolin binds to CPS. Sialic acid is known to inhibit alternative complement pathway activation, and, as expected, the bactericidal index (percentage of bacteria killed) for individual strains was inversely proportional to the sialic acid content of the CPS, and L-ficolin-initiated opsonophagocytic killing was significantly increased by addition of CPS-specific IgG2, which increased activation of the alternative pathway. We conclude that binding of L-ficolin/MASP complexes to the CPS generates C3 convertase C4b2a, which deposits C3b on GBS. C3b deposited by this lectin pathway forms alternative pathway C3 convertase C3bBb whose activity is enhanced by CPS-specific IgG2, leading to increased opsonophagocytic killing by further deposition of C3b on the GBS.
Distinct Calcium Channels Regulate Responses of Primary B Lymphocytes to B Cell Receptor Engagement and Mechanical Stimuli
Authors: Liu Qing-Hua , Liu Xiaohong , Wen Zhiyun , Hondowicz Brian , King Leslie , Monroe John , Freedman Bruce D. 
Published: April 2014

Abstract
Intracellular Ca2+ plays a central role in controlling lymphocyte function. Nonetheless, critical gaps remain in our understanding of the mechanisms that regulate its concentration. Although Ca2+-release-activated calcium (CRAC) channels are the primary Ca2+ entry pathways in T cells, additional pathways appear to be operative in B cells. Our efforts to delineate these pathways in primary murine B cells reveal that Ca2+-permeant nonselective cation channels (NSCCs) operate in a cooperative fashion with CRAC. Interestingly, these non-CRAC channels are selectively activated by mechanical stress, although the mechanism overlaps with BCR-activated pathways, suggesting that they may operate in concert to produce functionally diverse Ca2+ signals. NSCCs also regulate the membrane potential, which activates integrin-dependent binding of B cells to extracellular matrix elements involved in their trafficking and localization within secondary lymphoid organs. Thus, CRAC and distinct Ca2+ permeant NSCCs are differentially activated by the BCR and mechanical stimuli and regulate distinct aspects of B cell physiology.
Changes in the Novel Orphan, C5a Receptor (C5L2), during Experimental Sepsis and Sepsis in Humans
Authors: Huber-Lang Markus , Sarma J. Vidya , Rittirsch Daniel , Schreiber Heike , Weiss Manfred , Flierl Michael , Younkin Ellen , Schneider Marion , Suger-Wiedeck Heidemarie , Gebhard Florian , McClintock Shannon D. , Neff Thomas , Zetoune Firas , Bruckner Uwe , Guo Ren-Feng , Monk Peter N. , Ward Peter A. 
Published: April 2014

Abstract
Sepsis is associated with extensive complement activation, compromising innate immune defenses, especially in neutrophils (PMN). Recently, a second C5a receptor (C5L2) was detected on PMN without evidence of intracellular signaling. The current study was designed to determine changes in C5L2 in blood PMN during sepsis. In vitro exposure of PMN to C5a, but not to fMLP, led to reduced content of C5L2. Following cecal ligation and puncture-induced sepsis in rats, PMN demonstrated a time-dependent decrease in C5L2. In vivo blockade of C5a during experimental sepsis resulted in preservation of C5L2. Similarly, PMN from patients with progressive sepsis showed significantly reduced C5L2 expression (n = 26), which was virtually abolished in patients who developed multiorgan failure (n = 10). In contrast, sepsis survivors exhibited retention of C5L2 (n = 12/13). The data suggest that C5L2 on PMN diminishes during sepsis due to systemic generation of C5a, which is associated with a poor prognosis.
Requirement for CD28 May Not Be Absolute for Collagen-Induced Arthritis: Study with HLA-DQ8 Transgenic Mice
Authors: Taneja Veena , Taneja Neelam , Behrens Marshall , Griffiths Marie M. , Luthra Harvinder S. , David Chella S. 
Published: April 2014

Abstract
CD28 is required to achieve optimal T cell activation to an Ag. To determine the role CD28 costimulation plays in collagen-induced arthritis, we have generated DQ8 transgenic, CD28-deficient mice. DQ8 mice deficient for CD28 had comparable numbers of CD4 and CD8 T cells as DQ8.CD28+/+ mice. DQ8.CD28−/− mice develop collagen-induced arthritis with delayed onset and less severity than DQ8.CD28+/+ mice. T cells from DQ8.CD28−/− mice did not respond to type II collagen efficiently in vitro, although the response to DQ8-restricted peptides was similar to that in the parent mice. There was no functional defect in T cells as observed by proliferation with Con A. Cytokine analysis from in vitro study showed the production of high levels of the inflammatory cytokine, IFN-γ, in response to type II collagen. We observed an increase in CD4+CD28−NKG2D+ cells after immunization, suggesting an important role for cells bearing this receptor in the disease process. CD28−/− mice also have an increased number of DX5+ cells compared with CD28+/+ mice, which can lead to the production of high levels of IFN-γ. DQ8.CD28−/− mice had an increased number of cells bearing other costimulatory markers. Cells from DQ8.CD28−/− mice exhibited a lower proliferation rate and were resistant to activation-induced cell death compared with DQ8.CD28+/+ mice. This study supports the idea that CD28 plays a crucial role in the regulation of arthritis. However, in the absence of CD28 signaling, other costimulatory molecules can lead to the development of disease, thus indicating that the requirement for CD28 may not be absolute in the development of arthritis.
Leukotrienes: Underappreciated Mediators of Innate Immune Responses
Authors: Peters-Golden Marc , Canetti Claudio , Mancuso Peter , Coffey Michael J. 
Published: April 2014

AbstractLeukotrienes are bronchoconstrictor and vasoactive lipid mediators that are targets in the treatment of asthma. Although they are increasingly recognized to exert broad proinflammatory effects, their role in innate immune responses is less well appreciated. These molecules are indeed synthesized by resident and recruited leukocytes during infection. Acting via cell surface G protein-coupled receptors and subsequent intracellular signaling events, they enhance leukocyte accumulation, phagocyte capacity for microbial ingestion and killing, and generation of other proinflammatory mediators. Interestingly, a variety of acquired states of immunodeficiency, such as HIV infection and malnutrition, are characterized by a relative deficiency of leukotriene synthesis. The data reviewed herein point to leukotrienes as underappreciated yet highly relevant mediators of innate immunity.
Resolution of a 16.8-Mb Autoimmunity-Regulating Rat Chromosome 4 Region into Multiple Encephalomyelitis Quantitative Trait Loci and Evidence for Epistasis
Authors: Jagodic Maja , Marta Monica , Becanovic Kristina , Sheng Jian Rong , Nohra Rita , Olsson Tomas , Lorentzen Johnny C. 
Published: April 2014

Abstract
To investigate effects of a 16.8-Mb region on rat chromosome 4q42–43 on encephalomyelitis, we performed a high-resolution mapping using a 10th generation advanced intercross line between the susceptible DA strain and the MHC identical but resistant PVG.1AV1 strain. Clinical signs of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) developed in 29% of 772 F10 rats. Three regions controlling disease, Eae20, Eae21, and Eae22, were mapped using 15 microsatellite markers spanning 16.8 Mb. Eae20 was a major genetic determinant within the region whereas Eae21 modified disease severity. Eae22 was identified as an epistatic region because it only displayed an effect together with Piebald Virol Glaxo (PVG) alleles on Eae20. Disease down-regulation by PVG alleles in the telomeric part of Eae20 was also demonstrated in DA rats made congenic for a ∼1.44-Mb chromosomal region from PVG. As the region containing Eae20–Eae22 also regulates arthritis, together with the fact that the syntenic mouse 6F2–F3 region regulates experimental lupus and diabetes, and the syntenic human 12p13.31–13.2 region regulates multiple sclerosis and rheumatoid arthritis, the present data point to genes that control several inflammatory diseases. The pairscan analyses of interaction, which here identified Eae22, are novel in the encephalomyelitis field and of importance in the design of further studies of this region in other diseases and species. The limited number of genes identified in Eae20, Eae21, and Eae22 enables focused examination of their relevance in mechanistic animal studies and screening of their association to human diseases.