bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphine Impairs Host Innate Immune Response and Increases Susceptibility to Streptococcus pneumoniae Lung Infection
Authors: Wang Jinghua , Barke Roderick A. , Charboneau Richard , Roy Sabita 
Published: April 2014

Abstract
Chronic morphine use impairs host innate immune response and increases susceptibility to bacteria and virus. In this study a novel mouse model of chronic morphine treatment, followed by intranasal inoculation with Streptococcus pneumoniae, was used to investigate microbial events and host innate immune response. Our results show that chronic morphine treatment markedly delayed neutrophil recruitment and increased bacterial burden in the lung, spleen, and blood with a subsequent increase in mortality. In morphine-treated animals, before neutrophil recruitment, a significant decrease in TNF-α, IL-1, IL-6, MIP-2, and KC was observed both in bronchoalveolar lavage fluids and in lung tissue. In the early phase of infection, we found that accumulation of galectin-3 in the alveolar space of streptococcus-infected lungs was decreased after morphine treatment. The transcription factor NF-κB in lung resident cells was also inhibited after morphine treatment. Taken together, these results suggest that chronic morphine treatment in an S. pneumoniae infection model suppresses NF-κB gene transcription in lung resident cells, which, in turn, modulates the transcriptional regulation of MIP-2 and inflammatory cytokines. The decreased synthesis of MIP-2 and inflammatory cytokines coupled with the decreased release of galectin-3 result in reduced migration of neutrophils to the site of infection, thereby increasing susceptibility to S. pneumoniae infection after morphine treatment.
Enhanced Egg-Induced Immunopathology Correlates With High IFN-γ in Murine Schistosomiasis: Identification of Two Epistatic Genetic Intervals
Authors: Rutitzky Laura I. , Hernandez Hector J. , Yim Young-Sun , Ricklan David E. , Finger Eduardo , Mohan Chandra , Peter Inga , Wakeland Edward K. , Stadecker Miguel J. 
Published: April 2014

AbstractThe genetic basis of dissimilar immunopathology development among mouse strains infected with Schistosoma mansoni is not known. We performed a multipoint parametric linkage analysis on a cohort of F2 mice, offspring of brother-sister mating between (high pathology CBA × low pathology BL/6)F1 mice, to examine whether the observed differences in the type of immune response or the extent of hepatic immunopathology are linked to any particular genomic intervals. The F2 mice exhibited cytokine responses and immunopathologies that revealed a statistically significant correlation between prominent egg Ag-stimulated IFN-γ production by mesenteric lymph node cells and hepatic egg granuloma size. Increased IFN-γ production showed suggestive linkage to a dominant CBA locus on chromosome 1 and a recessive CBA locus on chromosome 5; significantly, there was an epistatic interaction between the two IFN-γ loci. An additional locus with suggestive linkage to granuloma formation and a CBA-recessive mode of inheritance was mapped to centromeric chromosome 13. Our analysis identified the first three genetic regions that appear to influence the immunopathology in murine schistosomiasis; however, further congenic dissection studies will furnish a more precise understanding of the genetic control of this disease.
In Vivo Ethanol Exposure Down-Regulates TLR2-, TLR4-, and TLR9-Mediated Macrophage Inflammatory Response by Limiting p38 and ERK1/2 Activation
Authors: Goral Joanna , Kovacs Elizabeth J. 
Published: April 2014

Abstract
Ethanol is known to increase susceptibility to infections, in part, by suppressing macrophage function. Through TLRs, macrophages recognize pathogens and initiate inflammatory responses. In this study, we investigated the effect of acute ethanol exposure on murine macrophage activation mediated via TLR2, TLR4, and TLR9. Specifically, the study focused on the proinflammatory cytokines IL-6 and TNF-α and activation of p38 and ERK1/2 MAPKs after a single in vivo exposure to physiologically relevant level of ethanol followed by ex vivo stimulation with specific TLR ligands. Acute ethanol treatment inhibited IL-6 and TNF-α synthesis and impaired p38 and ERK1/2 activation induced by TLR2, TLR4, and TLR9 ligands. We also addressed the question of whether ethanol treatment modified activities of serine/threonine-specific, tyrosine-specific phosphatases, and MAPK phosphatase type 1. Inhibitors of three families of protein phosphatases did not restore ethanol-impaired proinflammatory cytokine production nor p38 and ERK1/2 activation. However, inhibitors of serine/threonine protein phosphatase type 1 and type 2A significantly increased IL-6 and TNF-α levels, and prolonged activation of p38 and ERK1/2 when triggered by TLR4 and TLR9 ligands. In contrast, with TLR2 ligand stimulation, TNF-α production was reduced, whereas IL-6 levels, and p38 and ERK1/2 activation were not affected. In conclusion, acute ethanol exposure impaired macrophage responsiveness to multiple TLR agonists by inhibiting IL-6 and TNF-α production. Mechanism responsible for ethanol-induced suppression involved inhibition of p38 and ERK1/2 activation. Furthermore, different TLR ligands stimulated IL-6 and TNF-α production via signaling pathways, which showed unique characteristics.
Activation of Cytokine Production by Secreted Phospholipase A2 in Human Lung Macrophages Expressing the M-Type Receptor
Authors: Granata Francescopaolo , Petraroli Angelica , Boilard Eric , Bezzine Sofiane , Bollinger James , Del Vecchio Luigi , Gelb Michael H. , Lambeau Gerard , Marone Gianni , Triggiani Massimo 
Published: April 2014

Abstract
Secreted phospholipases A2 (sPLA2) are enzymes released in plasma and extracellular fluids during inflammatory diseases. Because human group IB and X sPLA2s are expressed in the lung, we examined their effects on primary human lung macrophages (HLM). Both sPLA2s induced TNF-α and IL-6 release in a concentration-dependent manner by increasing their mRNA expression. This effect was independent of their enzymatic activity because 1) the capacity of sPLA2s to mobilize arachidonic acid from HLM was unrelated to their ability to induce cytokine production; and 2) two catalytically inactive isoforms of group IB sPLA2 (bromophenacyl bromide-inactivated human sPLA2 and the H48Q mutant of the porcine sPLA2) were as effective as the catalytically active sPLA2s in inducing cytokine production. HLM expressed the M-type receptor for sPLA2s at both mRNA and protein levels, as determined by RT-PCR, immunoblotting, immunoprecipitation, and flow cytometry. Me-indoxam, which decreases sPLA2 activity as well as binding to the M-type receptor, suppressed sPLA2-induced cytokine production. Incubation of HLM with the sPLA2s was associated with phosphorylation of ERK1/2, and a specific inhibitor of this pathway, PD98059, significantly reduced the production of IL-6 elicited by sPLA2s. In conclusion, two distinct sPLA2s produced in the human lung stimulate cytokine production by HLM via a mechanism that is independent of their enzymatic activity and involves activation of the ERK1/2 pathway. HLM express the M-type receptor, but its involvement in eliciting cytokine production deserves further investigation.
Role of Complement and Complement Membrane Attack Complex in Laser-Induced Choroidal Neovascularization
Authors: Bora Puran S. , Sohn Jeong-Hyeon , Cruz Jose M. C. , Jha Purushottam , Nishihori Hiroki , Wang Yali , Kaliappan Sankaranarayanan , Kaplan Henry J. , Bora Nalini S. 
Published: April 2014

Abstract
Choroidal neovascularization (CNV), or choroidal angiogenesis, is the hallmark of age-related macular degeneration and a leading cause of visual loss after age 55. The pathogenesis of new choroidal vessel formation is poorly understood. Although inflammation has been implicated in the development of CNV, the role of complement in CNV has not been explored experimentally. A reliable way to produce CNV in animals is to rupture Bruch’s membrane with laser photocoagulation. A murine model of laser-induced CNV in C57BL/6 mice revealed the deposition of C3 and membrane attack complex (MAC) in the neovascular complex. CNV was inhibited by complement depletion using cobra venom factor and did not develop in C3−/− mice. Anti-murine C6 Abs in C57BL/6 mice inhibited MAC formation and also resulted in the inhibition of CNV. Vascular endothelial growth factor, TGF-β2, and β-fibroblast growth factor were elevated in C57BL/6 mice after laser-induced CNV; complement depletion resulted in a marked reduction in the level of these angiogenic factors. Thus, activation of complement, specifically the formation of MAC, is essential for the development of laser- induced choroidal angiogenesis in mice. It is possible that a similar mechanism may be involved in the pathophysiology of other angiogenesis essential diseases.
Plexin C1 Engagement on Mouse Dendritic Cells by Viral Semaphorin A39R Induces Actin Cytoskeleton Rearrangement and Inhibits Integrin-Mediated Adhesion and Chemokine-Induced Migration
Authors: Walzer Thierry , Galibert Laurent , Comeau Michael R. , De Smedt Thibaut 
Published: April 2014

Abstract
The poxvirus A39R protein is a member of the semaphorin family previously reported to bind plexin C1. We show that, in the mouse, plexin C1 is expressed on dendritic cells (DCs) and neutrophils and is the only receptor for A39R on these cells. The biological effects of a recombinant form of A39R were examined in vitro on mouse DCs derived from wild-type or plexin C1−/− mice. A39R binding to plexin C1 on DCs inhibited integrin-mediated adhesion and spreading in vitro. This phenomenon was accompanied by a decrease in integrin signaling, measured by focal adhesion kinase phosphorylation, and a rearrangement of the actin cytoskeleton, without inducing DC maturation or affecting their viability. The A39R effect on DC adhesion was blocked by a specific inhibitor of cofilin phosphorylation, suggesting that the regulation of F-actin turnover by plexin C1 was essential to induce cellular retraction. Furthermore, A39R binding to plexin C1 inhibited chemokine-induced migration of DCs in vitro, suggesting that plexins and semaphorins could be involved in the regulation of leukocyte movement.
Macrophages Expressing Triggering Receptor Expressed on Myeloid Cells-1 Are Underrepresented in the Human Intestine
Authors: Schenk Mirjam , Bouchon Axel , Birrer Stefan , Colonna Marco , Mueller Christoph 
Published: April 2014

Abstract
Triggering receptor expressed on myeloid cells (TREM)-1 is a cell surface molecule on neutrophils and monocytes/macrophages implicated in the amplification of inflammatory responses by enhancing degranulation and secretion of proinflammatory mediators. Macrophages play an important role in the intestinal mucosal immune system, because they are preferentially localized in the subepithelial region. Despite the presence of enormous numbers of bacteria in the colonic mucosa and the close proximity between mucosal macrophages and luminal bacteria, the intestinal mucosa normally displays minimal signs of inflammation. In this study, we show that the resident macrophage population in normal human small and large intestine contains only few TREM-1-expressing macrophages (&lt;10%), whereas the overwhelming majority of monocytes (&gt;90%) and macrophages from lymph nodes or tonsils (&gt;80%) express TREM-1 on the cell surface. These findings were confirmed by FACS analysis and immunostainings of frozen tissue sections. The differential expression of TREM-1 greatly affects the functional capacities of monocytes and tissue macrophages. Although monocytes and macrophages from spleen, lymph nodes, or tonsils show a substantial increase in oxidative burst after TREM-1 cross-linking, no effect is seen in intestinal macrophages. Intriguingly, in contrast to monocytes, intestinal macrophages fail to up-regulate TREM-1 in response to TNF. This refractory state may be induced in intestinal macrophages by the local presence of IL-10 and TGF-β, because these two immunoregulatory cytokines synergistically down-regulate TREM-1 expression on monocytes in vitro. The absence of TREM-1 expression on lamina propria macrophages is likely to prevent excessive inflammatory reactions, and thus, excessive tissue damage in the intestine.
Genetic Interactions in Eae2 Control Collagen-Induced Arthritis and the CD4+/CD8+ T Cell Ratio
Authors: Karlsson Jenny , Johannesson Martina , Lindvall Therese , Wernhoff Patrik , Holmdahl Rikard , Andersson Åsa 
Published: April 2014

Abstract
The Eae2 locus on mouse chromosome 15 controls the development of experimental autoimmune encephalomyelitis (EAE); however, in this study we show that it also controls collagen-induced arthritis (CIA). To find the smallest disease-controlling locus/loci within Eae2, we have studied development of CIA in 676 mice from a partially advanced intercross. Eae2 congenic mice were bred with mice congenic for the Eae3/Cia5 locus on chromosome 3, previously shown to interact with Eae2. To create a large number of genetic recombinations within the congenic fragments, the offspring were intercrossed, and the eight subsequent generations were analyzed for CIA. We found that Eae2 consists of four Cia subloci (Cia26, Cia30, Cia31, and Cia32), of which two interacted with each other, conferring severe CIA. Genes within the other two loci independently interacted with genes in Eae3/Cia5. Investigation of the CD4/CD8 T cell ratio in mice from the partially advanced intercross shows that this trait is linked to one of the Eae2 subloci through interactions with Eae3/Cia5. Furthermore, the expression of CD86 on stimulated macrophages is linked to Eae2.
Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival
Authors: Adams Andrew B. , Shirasugi Nozomu , Jones Thomas R. , Durham Megan M. , Strobert Elizabeth A. , Cowan Shannon , Rees Phyllis , Hendrix Rose , Price Karen , Kenyon Norma S. , Hagerty David , Townsend Robert , Hollenbaugh Dianne , Pearson Thomas C. , Larsen Christian P. 
Published: April 2014

Abstract
In recent years, reagents have been developed that specifically target signals critical for effective T cell activation and function. Manipulation of the CD28/CD80/86 and CD40/CD154 pathways has exhibited extraordinary efficacy, particularly when the pathways are blocked simultaneously. Despite the reported efficacy of anti-CD154 in rodents and higher models, its future clinical use is uncertain due to reported thromboembolic events in clinical trials. To circumvent this potential complication, we developed and evaluated a chimeric Ab targeting CD40 (Chi220, BMS-224819) as an alternative to CD154. Although Chi220 blocks CD154 binding, it also possesses partial agonist properties and weak stimulatory potential. The anti-CD40 was tested alone and in combination with a rationally designed, high affinity variant of CTLA4-Ig, LEA29Y (belatacept), in a nonhuman primate model of islet transplantation. Although either agent alone only modestly prolonged islet survival (Chi220 alone: 14, 16, and 84 days; LEA29Y alone: 58 and 60 days), their combination (LEA29Y and Chi220) dramatically facilitated long term survival (237, 237, 220, &gt;185, and 172 days). We found that the effects of Chi220 treatment were not mediated solely through deletion of CD20-bearing cells and that the combined therapy did not significantly impair established antiviral immunity.
Ontogeny and Regulation of IL-7-Expressing Thymic Epithelial Cells
Authors: Zamisch Monica , Moore-Scott Billie , Su Dong-ming , Lucas Philip J. , Manley Nancy , Richie Ellen R. 
Published: April 2014

Abstract
Epithelial cells in the thymus produce IL-7, an essential cytokine that promotes the survival, differentiation, and proliferation of thymocytes. We identified IL-7-expressing thymic epithelial cells (TECs) throughout ontogeny and in the adult mouse thymus by in situ hybridization analysis. IL-7 expression is initiated in the thymic fated domain of the early primordium by embryonic day 11.5 and is expressed in a Foxn1-independent pathway. Marked changes occur in the localization and regulation of IL-7-expressing TECs during development. IL-7-expressing TECs are present throughout the early thymic rudiment. In contrast, a major population of IL-7-expressing TECs is localized to the medulla in the adult thymus. Using mouse strains in which thymocyte development is arrested at various stages, we show that fetal and postnatal thymi differ in the frequency and localization of IL-7-expressing TECs. Whereas IL-7 expression is initiated independently of hemopoietic-derived signals during thymic organogenesis, thymocyte-derived signals play an essential role in regulating IL-7 expression in the adult TEC compartment. Moreover, different thymocyte subsets regulate the expression of IL-7 and keratin 5 in adult cortical epithelium, suggesting that despite phenotypic similarities, the cortical TEC compartments of wild-type and RAG-1−/− mice are developmentally and functionally distinct.
Peptide-Specific Intercellular Transfer of MHC Class II to CD4+ T Cells Directly from the Immunological Synapse upon Cellular Dissociation
Authors: Wetzel Scott A. , McKeithan Timothy W. , Parker David C. 
Published: April 2014

Abstract
The transfer of membrane proteins from APC to T cells was initially described in the 1970s, and subsequent work has described two mechanisms of transfer: APC-derived exosomes and direct transfer of small packets, while cells remain conjugated. Using fibroblast APC expressing a GFP-tagged I-Ek molecule with covalently attached antigenic peptide, we observed a third mechanism in live cell imaging: T cells spontaneously dissociating from APC often capture MHC:peptide complexes directly from the immunological synapse. Using two I-Ek-restricted murine TCR transgenic T cells with different peptide specificity, we show in this study that the MHC transfer is peptide specific. Using blocking Abs, we found that MHC:peptide transfer in this system requires direct TCR-MHC:peptide interactions and is augmented by costimulation through CD28-CD80 interactions. Capture of the GFP-tagged MHC:peptide complexes correlates with an activated phenotype of the T cell, elevated CD69 with down-modulated TCR. The transferred MHC:peptide molecules transferred to the T cell are associated with molecules that imply continued TCR signaling; p56lck, phosphotyrosine, and polarization of the actin cytoskeleton.
Type I IFN Negatively Regulates CD8+ T Cell Responses through IL-10-Producing CD4+ T Regulatory 1 Cells
Authors: Dikopoulos Nektarios , Bertoletti Antonio , Kröger Andrea , Hauser Hansjörg , Schirmbeck Reinhold , Reimann Jörg 
Published: April 2014

Abstract
Pleiotropic, immunomodulatory effects of type I IFN on T cell responses are emerging. We used vaccine-induced, antiviral CD8+ T cell responses in IFN-β (IFN-β−/−)- or type I IFN receptor (IFNAR−/−)-deficient mice to study immunomodulating effects of type I IFN that are not complicated by the interference of a concomitant virus infection. Compared with normal B6 mice, IFNAR−/− or IFN-β−/− mice have normal numbers of CD4+ and CD8+ T cells, and CD25+FoxP3+ T regulatory (TR) cells in liver and spleen. Twice as many CD8+ T cells specific for different class I-restricted epitopes develop in IFNAR−/− or IFN-β−/− mice than in normal animals after peptide- or DNA-based vaccination. IFN-γ and TNF-α production and clonal expansion of specific CD8+ T cells from normal and knockout mice are similar. CD25+FoxP3+ TR cells down-modulate vaccine-primed CD8+ T cell responses in normal, IFNAR−/−, or IFN-β−/− mice to a comparable extent. Low IFN-α or IFN-β doses (500–103 U/mouse) down-modulate CD8+ T cells priming in vivo. IFNAR- and IFN-β-deficient mice generate 2- to 3-fold lower numbers of IL-10-producing CD4+ T cells after polyclonal or specific stimulation in vitro or in vivo. CD8+ T cell responses are thus subjected to negative control by both CD25+FoxP3+ TR cells and CD4+IL-10+ TR1 cells, but only development of the latter TR cells depends on type I IFN.
Abnormal Th1 Cell Differentiation and IFN-γ Production in T Lymphocytes from Motheaten Viable Mice Mutant for Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-1
Authors: Yu Wen-Mei , Wang Siying , Keegan Achsah D. , Williams Mark S. , Qu Cheng-Kui 
Published: April 2014

Abstract
Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) plays an important role in T and B lymphocyte signaling; however, the function of SHP-1 in Th cell differentiation, in particular, the Th1 response, has not been defined. In this study, we provide evidence that SHP-1 phosphatase negatively regulates Th1 cell development and IFN-γ production. Compared with the wild-type control, anti-CD3-activated mouse T lymphocytes carrying the motheaten viable mutation in the SHP-1 gene produced a significantly increased amount of IFN-γ in the presence of IL-12. This increase was also seen at the basal level without IL-12 addition. Similarly, Th1 cell differentiation and proliferation of anti-CD3-activated SHP-1 mutant lymph node cells in the presence or absence of IL-12 were markedly enhanced, indicating a negative role for SHP-1 phosphatase in such lymphocyte activities. Interestingly, IL-12-induced activation of Jak2 and STAT4, critical components for IL-12-mediated cellular responses, was shortened or attenuated in mutant T cells. Together these results suggest that SHP-1 negatively regulates Th1 cell development and functions through a mechanism that is not directly related to IL-12 signaling.
Functional Heterogeneity of Memory CD4 T Cell Responses in Different Conditions of Antigen Exposure and Persistence
Authors: Harari Alexandre , Vallelian Florence , Meylan Pascal R. , Pantaleo Giuseppe 
Published: April 2014

Abstract
Memory CD4 T cell responses are functionally and phenotypically heterogeneous. In the present study, memory CD4 T cell responses were analyzed in different models of Ag-specific immune responses differing on Ag exposure and/or persistence. Ag-specific CD4 T cell responses for tetanus toxoid, HSV, EBV, CMV, and HIV-1 were compared. Three distinct patterns of T cell response were observed. A dominant single IL-2 CD4 T cell response was associated with the model in which the Ag can be cleared. Polyfunctional (single IL-2 plus IL-2/IFN-γ plus single IFN-γ) CD4 T cell responses were associated with Ag persistence and low Ag levels. A dominant single IFN-γ CD4 T cell response was associated with the model of Ag persistence and high Ag levels. The results obtained supported the hypothesis that the different patterns observed were substantially influenced by different conditions of Ag exposure and persistence.
Cutting Edge: Macrophage Inhibition by Cyclic AMP (cAMP): Differential Roles of Protein Kinase A and Exchange Protein Directly Activated by cAMP-1
Authors: Aronoff David M. , Canetti Claudio , Serezani Carlos H. , Luo Ming , Peters-Golden Marc 
Published: April 2014

Abstract
cAMP has largely inhibitory effects on components of macrophage activation, yet downstream mechanisms involved in these effects remain incompletely defined. Elevation of cAMP in alveolar macrophages (AMs) suppresses FcγR-mediated phagocytosis. We now report that protein kinase A (PKA) inhibitors (H-89, KT-5720, and myristoylated PKA inhibitory peptide 14–22) failed to prevent this suppression in rat AMs. We identified the expression of the alternative cAMP target, exchange protein directly activated by cAMP-1 (Epac-1), in human and rat AMs. Using cAMP analogs that are highly specific for PKA (N6-benzoyladenosine-3′,5′-cAMP) or Epac-1 (8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cAMP), we found that activation of Epac-1, but not PKA, dose-dependently suppressed phagocytosis. By contrast, activation of PKA, but not Epac-1, suppressed AM production of leukotriene B4 and TNF-α, whereas stimulation of either PKA or Epac-1 inhibited AM bactericidal activity and H2O2 production. These experiments now identify Epac-1 in primary macrophages, and define differential roles of Epac-1 vs PKA in the inhibitory effects of cAMP.