bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Sphingosine Kinase in a Murine Model of Allergic Asthma
Authors: Lai Wen-Qi , Goh Hong Heng , Bao Zhang , Wong W. S. Fred , Melendez Alirio J. , Leung Bernard P. 
Published: April 2014

Abstract
Asthma is an allergic disease characterized by chronic airway eosinophilia and pulmonary infiltration of lymphocytes, particularly of the Th2 subtype, macrophages and mast cells. Previous studies have shown a pivotal role for sphingosine kinase (SphK) on various proinflammatory cells, such as lymphocyte and eosinophil migration and mast cell degranulation. We therefore examined the roles of SphK in a murine model of allergic asthma. In mice previously sensitized to OVA, i.p. administration of N,N-dimethylsphingosine (DMS), a potent SphK inhibitor, significantly reduced the total inflammatory cell infiltrate and eosinophilia and the IL-4, IL-5, and eotaxin levels in bronchoalveolar lavage fluid in response to inhaled OVA challenge. In addition, DMS significantly suppressed OVA-induced inflammatory infiltrates and mucus production in the lungs, and airway hyperresponsiveness to methacholine in a dose-dependent manner. OVA-induced lymphocyte proliferation and IL-4 and IL-5 secretion were reduced in thoracic lymph node cultures from DMS-treated mice. Moreover, similar reduction in inflammatory infiltrates, bronchoalveolar lavage, IL-4, IL-5, eotaxin, and serum OVA-specific IgE levels was observed in mice with SphK1 knock-down via small interfering RNA approach. Together, these data demonstrate the therapeutic potential of SphK modulation in allergic airways disease.
Inhibition of TLR Activation and Up-Regulation of IL-1R-Associated Kinase-M Expression by Exogenous Gangliosides
Authors: Shen Weiping , Stone Kelly , Jales Alessandra , Leitenberg David , Ladisch Stephan 
Published: April 2014

AbstractGangliosides, sialic acid-containing glycosphingolipids present in the outer leaflet of plasma membranes, are produced at high levels by some tumors, are actively shed into the tumor microenvironment, and can be detected in high concentrations in the serum of cancer patients. These tumor-shed molecules are known to be immunosuppressive, although mechanisms remain to be fully elucidated. In this study, we show that membrane enrichment of human monocytes with purified exogenous gangliosides potently inhibits ligand-induced activation and proinflammatory cytokine production induced by a broad range of TLRs, including TLR2, TLR3, TLR6, and TLR7/8, in addition to a previously identified inhibitory effect on TLR4 and TLR5. Inhibition of TLR activation is reversible, with complete restoration of TLR signaling within 6–24 h of washout of exogenous gangliosides, and is selective for certain gangliosides (GM1, GD1a, and GD1b), whereas others (GM3) are inactive. To characterize the inhibition, we assessed the expression of the TLR signaling pathway inhibitor, IL-1 receptor associated kinase-M (IRAK-M). In response to ganglioside enrichment alone, we observed striking up-regulation of IRAK-M in monocytes, but without concomitant proinflammatory cytokine production. This contrasts with endotoxin tolerance, in which IRAK-M up-regulation follows proinflammatory cytokine expression caused by LPS exposure. We hypothesize that ganglioside treatment induces a state of tolerance to TLR signaling, leading to blunted activation of innate immune responses. In the tumor microenvironment, shed tumor ganglioside enrichment of APC membranes may likewise cause these cells to bypass the normal TLR signaling response and progress directly to the inhibitory state.
Gastrointestinal Dendritic Cells Promote Th2 Skewing via OX40L
Authors: Blázquez Ana Belén , Berin M. Cecilia 
Published: April 2014

AbstractMice can be sensitized to food proteins by oral administration with the adjuvant cholera toxin (CT), such that they undergo anaphylaxis when rechallenged with the sensitizing allergen. In contrast, feeding of Ags alone leads to oral tolerance. Our aim was to define the mechanisms by which gastrointestinal dendritic cells (DCs) participate in the deviation of tolerance to allergic sensitization in the gut in response to CT. BALB/c mice were fed with CT or PBS. The impact of CT on DC subsets in the mesenteric lymph node (MLN) was assessed by flow cytometry. Ag presentation assays were performed with DCs isolated from the MLN of PBS- or CT-fed mice, using OVA-specific CD4+ T cells as responder cells. Gene expression in MLN DCs was determined by real-time PCR, and neutralizing Abs were used to test the function of OX40 ligand (OX40L) in Th2 skewing. Oral administration of CT induced an increase in the total CD11c+ population in the MLN. CT induced a selective increase in migration of the CD11c+CD11b−CD8α− DC subset and the maturation of all DC subsets. Maturation of DCs in vivo enhanced T cell proliferation and cytokine secretion. Oral CT induced up-regulation of Jagged-2 and OX40L by MLN DCs. Neutralizing anti-OX40L Abs completely abrogated the CT-induced Th2 cytokine response. We show that oral CT induces selective DC migration, maturation, and T cell priming activity in the MLN. Th2 skewing is mediated by OX40L, and we speculate that this molecule may be an important inducer of allergic sensitization to food allergens.
De Novo Production of K-α1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection
Authors: Goers Trudie A. , Ramachandran Sabarinathan , Aloush Aviva , Trulock Elbert , Patterson G. Alexander , Mohanakumar Thalachallour 
Published: April 2014

AbstractLung transplantation is the treatment option for a variety of end-stage pulmonary diseases. Posttransplant development of Abs against donor HLA and non-HLA Ags have been associated with acute and chronic rejection of transplanted organs. Development of bronchiolitis obliterans syndrome (BOS) following lung transplantation has been correlated with de novo production of anti-donor-HLA Abs. However, only a portion of the patients with BOS demonstrate detectable anti-donor-HLA Abs. Airway epithelium is considered as a major target for lung allograft rejection. In this study we demonstrate that many BOS+ patients (12 of 36) develop Abs reactive to epithelial cell Ag that are distinct from HLA. Furthermore, de novo production of antiepithelial cell Ab precedes clinical onset of BOS. N-terminal sequencing and blastx analysis as well as blocking with K-α1 tubulin-specific Ab identified the epithelial Ag as K-α1 tubulin. Binding of the de novo-produced anti-K-α1 tubulin Abs to the airway epithelial cells resulted in the increased expression of transcription factors (TCF5 and c-Myc), leading to increased expression of fibrogenic growth factors, activation of cell cycle signaling, and fibroproliferation, the central events in immunopathogenesis of BOS following human lung transplantation.
Aberrant Genetic Control of Invariant TCR-Bearing NKT Cell Function in New Zealand Mouse Strains: Possible Involvement in Systemic Lupus Erythematosus Pathogenesis
Authors: Tsukamoto Kazuyuki , Ohtsuji Mareki , Shiroiwa Wakana , Lin Qingshun , Nakamura Kazuhiro , Tsurui Hiromichi , Jiang Yi , Sudo Katsuko , Nishimura Hiroyuki , Shirai Toshikazu , Hirose Sachiko 
Published: April 2014

AbstractBoth suppressive and promoting roles of NKT cells have been reported in the pathogenesis of systemic lupus erythematosus (SLE). Herein, we found that although New Zealand mice have normal frequencies of NKT cells, their in vitro potential to produce IL-4 and IFN-γ in response to α-galactosylceramide was remarkably impaired in New Zealand Black (NZB) mice prone to mild SLE, while production was highly up-regulated in nonautoimmune New Zealand White (NZW) mice and at intermediate levels in (NZB × NZW)F1 mice, which are prone to severe SLE. Because this aberration is evident in young mice before disease onset, genetic mechanisms are thought to be involved. Genome-wide quantitative trait locus analysis and association studies revealed that a locus linked to D11Mit14 on chromosome 11 may be involved in the difference in cytokine-producing potential between NZB and NZW NKT cells. Additionally, (NZB × NZW)F1 × NZB backcross progeny with the NZW genotype for D11Mit14 showed significantly increased frequencies of age-associated SLE phenotypes, such as high serum levels of IgG, IgG anti-DNA Abs, and lupus nephritis. In coculture studies, α-galactosylceramide-stimulated NKT cells from NZW and (NZB × NZW)F1 mice, but not from NZB mice, showed significantly enhanced Ig synthesis by B cells. These findings suggest that the D11Mit14-linked NZW locus may contribute to the development of SLE in (NZB × NZW)F1 mice through a mechanism that up-regulates NKT cell function. Thus, this NZW allele may be a candidate of the NZW modifiers that act to promote (NZB × NZW)F1 disease.
Mast Cell Migration from the Skin to the Draining Lymph Nodes upon Ultraviolet Irradiation Represents a Key Step in the Induction of Immune Suppression
Authors: Byrne Scott N. , Limón-Flores Alberto Y. , Ullrich Stephen E. 
Published: April 2014

AbstractThe UV radiation in sunlight is the primary cause of skin cancer. UV is also immunosuppressive and numerous studies have shown that UV-induced immune suppression is a major risk factor for skin cancer induction. Previous studies demonstrated that dermal mast cells play a critical role in the induction of immune suppression. Mast cell-deficient mice are resistant to the immunosuppressive effects of UV radiation, and UV-induced immune suppression can be restored by injecting bone marrow-derived mast cells into the skin of mast cell- deficient mice. The exact process however, by which mast cells contribute to immune suppression, is not known. In this study, we show that one of the first steps in the induction of immune suppression is mast cell migration from the skin to the draining lymph nodes. UV exposure, in a dose-dependent manner, causes a significant increase in lymph node mast cell numbers. When GFP+ skin was grafted onto mast cell-deficient mice, we found that GFP+ mast cells preferentially migrated into the lymph nodes draining the skin. The mast cells migrated primarily to the B cell areas of the draining nodes. Mast cells express CXCR4+ and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression. Our findings indicate that UV-induced mast cell migration to draining lymph nodes, mediated by CXCR4 interacting with CXCL12, represents a key early step in UV-induced immune suppression.
Combined CXCR3/CCR5 Blockade Attenuates Acute and Chronic Rejection
Authors: Schnickel Gabriel T. , Bastani Sam , Hsieh George R. , Shefizadeh Ali , Bhatia Rubina , Fishbein Michael C. , Belperio John , Ardehali Abbas 
Published: April 2014

Abstract
Chemokine-chemokine receptor interactions orchestrate mononuclear cells recruitment to the allograft, leading to acute and chronic rejection. Despite biologic redundancy, several experimental studies have demonstrated the importance of CXCR3 and CCR5 in acute rejection of allografts. In these studies, deficiency or blockade of CXCR3 or CCR5 led to prolongation of allograft survival, yet allografts were ultimately lost to acute rejection. Given the above findings and the specificity of mononuclear cells bearing CXCR3 and CCR5, we hypothesized that combined blockade of CXCR3 and CCR5 will lead to indefinite (&gt;100 days) graft survival in a full MHC-mismatched murine cardiac allograft model. The donor hearts in the control group were rejected in 6 ± 1 days after transplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival &gt;15-fold vs the control group; all allografts survived for &gt;100 days. More importantly, the donor hearts did not display any intimal lesions characteristic of chronic rejection. Further analysis of the donor hearts in the CXCR3/CCR5 blockade group demonstrated graft infiltration with CD4+CD25+ T cells expressing the Foxp3 gene. Depletion of CD25+ cells in the combined CXCR3 and CCR5 blockade group resulted in acute rejection of the allografts in 22 ± 2 days. Combined CXCR3 and CCR5 blockade also reduced alloantigen-specific T lymphocyte proliferation. Combined CXCR3 and CCR5 blockade is effective in preventing acute and chronic rejection in a robust murine model. This effect is mediated, in part, by CD25+ regulatory T cell recruitment and control of T lymphocyte proliferation.
Isoform-Specific Inhibition of RORα-Mediated Transcriptional Activation by Human FOXP3
Authors: Du Jianguang , Huang Chunjian , Zhou Baohua , Ziegler Steven F. 
Published: April 2014

Abstract
FOXP3 is a forkhead family transcriptional repressor important for the development and function of CD4+CD25+ regulatory T cells. In humans, FOXP3 is expressed as two isoforms, a full-length form and a smaller form lacking exon 2. These two isoforms are expressed in approximately equal amounts in circulating regulatory T cells, and are induced equally in freshly activated CD4+CD25− T cells. Herein, we show that FOXP3 interacts with retinoic acid receptor-related orphan receptor (ROR)α, and that this interaction inhibits transcriptional activation mediated by RORα. Full-length FOXP3, but not the isoform lacking exon 2, interacts with RORα, and the region of FOXP3 involved in the interaction is encoded by exon 2. Mutation of the LxxLL motif in FOXP3, located in exon 2, abolished interaction and repression by FOXP3. Additionally, the inhibition of RORα by FOXP3 does not require an intact forkhead domain, demonstrating a mode of FOXP3 function that is independent of DNA binding. Interestingly, expression of RORα in T cells leads to the expression of genes that define Th17 cells, and the expression of each of these gene was inhibited by coexpression of full-length, but not ΔEx2, FOXP3. These data expand the possible targets of FOXP3-mediated repression and demonstrate functional differences between FOXP3 isoforms.
Intercellular Adhesion Molecule-3 Binding of Integrin αLβ2 Requires Both Extension and Opening of the Integrin Headpiece
Authors: Tang Xiao-Yan , Li Yan-Feng , Tan Suet-Mien 
Published: April 2014

Abstract
The leukocyte-restricted integrin αLβ2 is required in immune processes such as leukocyte adhesion, migration, and immune synapse formation. Activation of αLβ2 by conformational changes promotes αLβ2 binding to its ligands, ICAMs. It was reported that different affinity states of αLβ2 are required for binding ICAM-1 and ICAM-3. Recently, the bent, extended with a closed headpiece, and extended with open headpiece conformations of αLβ2, was reported. To address the overall conformational requirements of αLβ2 that allow selective binding of these ICAMs, we examined the adhesion properties of these αLβ2 conformers. αLβ2 with different conformations were generated by mutations, and verified by using a panel of reporter mAbs that detect αLβ2 extension, hybrid domain movement, or I-like domain activation. We report a marked difference between extended αLβ2 with closed and open headpieces in their adhesive properties to ICAM-1 and ICAM-3. Our data show that the extension of αLβ2 alone is sufficient to mediate ICAM-1 adhesion. By contrast, an extended αLβ2 with an open headpiece is required for ICAM-3 adhesion.
Leishmania major-Specific B Cells Are Necessary for Th2 Cell Development and Susceptibility toL. majorLV39 in BALB/c Mice
Authors: Ronet Catherine , Voigt Heike , Himmelrich Hayo , Doucey Marie-Agnès , Hauyon-La Torre Yazmin , Revaz-Breton Mélanie , Tacchini-Cottier Fabienne , Bron Claude , Louis Jacques , Launois Pascal 
Published: April 2014

AbstractB lymphocytes are considered to play a minimal role in host defense against Leishmania major. In this study, the contribution of B cells to susceptibility to infection with different strains of L. major was investigated in BALB/c mice lacking mature B cells due to the disruption of the IgM transmembrane domain (μMT). Whereas BALB/c μMT remained susceptible to infection with L. major IR173 and IR75, they were partially resistant to infection with L. major LV39. Adoptive transfer of naive B cells into BALB/c μMT mice before infection restored susceptibility to infection with L. major LV39, demonstrating a role for B cells in susceptibility to infection with this parasite. In contrast, adoptive transfer of B cells that express an IgM/IgD specific for hen egg lysozyme (HEL), an irrelevant Ag, did not restore disease progression in BALB/c μMT mice infected with L. major LV39. This finding was likely due to the inability of HEL Tg B cells to internalize and present Leishmania Ags to specific T cells. Furthermore, specific Ig did not contribute to disease progression as assessed by transfer of immune serum in BALB/c μMT mice. These data suggest that direct Ag presentation by specific B cells and not Ig effector functions is involved in susceptibility of BALB/c mice to infection with L. major LV39.
CD209+ Macrophages Mediate Host Defense against Propionibacterium acnes
Authors: Liu Philip T. , Phan Jenny , Tang Dominic , Kanchanapoomi Melissa , Hall Brian , Krutzik Stephan R. , Kim Jenny 
Published: April 2014

Abstract
Propionibacterium acnes is a major etiological factor of acne, triggering an inflammatory response in part through the activation of TLR2. In this study, we demonstrate that activation of peripheral blood monocytes with P. acnes in vitro induced their differentiation into two distinct innate immune cell subsets, CD209+ macrophages and CD1b+ dendritic cells. Furthermore, P. acnes induced expression of mRNA for the cytokines IL-15 and GM-CSF, which differentiate CD209+ and CD1b+ cells, respectively. The CD209+ cells were more effective in uptake of P. acnes, compared with the CD1b+ cells, and demonstrated a 2-fold greater antimicrobial activity against the phagocytosed bacteria. Although CD1b+ cells secreted inflammatory cytokines in response to both P. acnes and a TLR2 ligand control, the CD209+ cells responded only to P. acnes. The addition of all-trans retinoic acid, a commonly used agent for the treatment of acne, directly induced differentiation of monocytes into CD209+ macrophages and enhanced the P. acnes-mediated differentiation of the CD209+ subset. Therefore, the differentiation of monocytes into CD209+ macrophages and CD1b+ dendritic cells distinctly mediate the innate immune response to P. acnes.
IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2−/− Mice via Peroxisome Proliferator-Activated Receptor-γ Activation
Authors: Coste Agnès , Lagane Céline , Filipe Cédric , Authier Hélène , Galès Amandine , Bernad José , Douin-Echinard Victorine , Lepert Jean-Claude , Balard Patricia , Linas Marie-Denise , Arnal Jean-François , Auwerx Johan , Pipy Bernard 
Published: April 2014

AbstractWe recently demonstrated that in vitro peroxisome proliferator-activated receptor-γ (PPARγ) activation of mouse peritoneal macrophages by IL-13 or PPARγ ligands promotes uptake and killing of Candida albicans through mannose receptor overexpression. In this study, we demonstrate that i.p. treatment of immunocompetent and immunodeficient (RAG-2−/−) mice with natural and synthetic PPARγ-specific ligands or with IL-13 decreases C. albicans colonization of the gastrointestinal (GI) tract 8 days following oral infection with the yeast. We also showed that Candida GI infection triggers macrophage recruitment in cecum mucosa. These mucosal macrophages, as well as peritoneal macrophages, overexpress the mannose receptor after IL-13 and rosiglitazone treatments. The treatments promote macrophage activation against C. albicans as suggested by the increased ability of peritoneal macrophages to phagocyte C. albicans and to produce reactive oxygen intermediates after yeast challenge. These effects on C. albicans GI infection and on macrophage activation are suppressed by treatment of mice with GW9662, a selective PPARγ antagonist, and are reduced in PPARγ+/− mice. Overall, these data demonstrate that IL-13 or PPARγ ligands attenuate C. albicans infection of the GI tract through PPARγ activation and hence suggest that PPARγ ligands may be of therapeutic value in esophageal and GI candidiasis in immunocompromised patients.
Suppression of Proteoglycan-Induced Arthritis by Anti-CD20 B Cell Depletion Therapy Is Mediated by Reduction in Autoantibodies and CD4+ T Cell Reactivity
Authors: Hamel Keith , Doodes Paul , Cao Yanxia , Wang Yumei , Martinson Jeffrey , Dunn Robert , Kehry Marilyn R. , Farkas Balint , Finnegan Alison 
Published: April 2014

AbstractB cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) since the discovery of RA as an autoimmune disease. There is renewed interest in B cells in RA based on the clinical efficacy of B cell depletion therapy in RA patients. Although, reduced titers of rheumatoid factor and anti-cyclic citrullinated peptide Abs are recorded, the mechanisms that convey clinical improvement are incompletely understood. In the proteoglycan-induced arthritis (PGIA) mouse model of RA, we reported that Ag-specific B cells have two important functions in the development of arthritis. PG-specific B cells are required as autoantibody-producing cells as well as Ag-specific APCs. Herein we report on the effects of anti-CD20 mAb B cell depletion therapy in PGIA. Mice were sensitized to PG and treated with anti-CD20 Ab at a time when PG-specific autoantibodies and T cell activation were evident but before acute arthritis. In mice treated with anti-CD20 mAb, development of arthritis was significantly reduced in comparison to control mAb-treated mice. B cell depletion reduced the PG-specific autoantibody response. Furthermore, there was a significant reduction in the PG-specific CD4+ T cell recall response as well as significantly fewer PG-specific CD4+ T cells producing IFN-γ and IL-17, but not IL-4. The reduction in PG-specific T cells was confirmed by the inability of CD4+ T cells from B cell-depleted mice to adoptively transfer disease into SCID mice. Overall, B cell depletion during PGIA significantly reduced disease and inhibited both autoreactive B cell and T cell function.
The Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses
Authors: Kielian Tammy , Syed Mohsin Md. , Liu Shuliang , Phulwani Nirmal K. , Phillips Napoleon , Wagoner Gail , Drew Paul D. , Esen Nilufer 
Published: April 2014

Abstract
Brain abscesses result from a pyogenic parenchymal infection commonly initiated by Gram-positive bacteria such as Staphylococcus aureus. Although the host immune response elicited following infection is essential for effective bacterial containment, this response also contributes to the significant loss of brain parenchyma by necrosis that may be reduced by modulating the inflammatory response. Ciglitazone, a PPAR-γ agonist with anti-inflammatory properties, was evaluated for its ability to influence the course of brain abscess development when treatment was initiated 3 days following infection. Interestingly, abscess-associated bacterial burdens were significantly lower following ciglitazone administration, which could be explained, in part, by the finding that ciglitazone enhanced S. aureus phagocytosis by microglia. In addition, ciglitazone attenuated the expression of select inflammatory mediators during brain abscess development including inducible NO synthase, TNF-α, IL-1β, CXCL2, and CCL3. Unexpectedly, ciglitazone also accelerated brain abscess encapsulation, which was typified by the heightened expression of fibronectin and α-smooth muscle actin-positive myofibroblasts. Collectively, through its ability to attenuate excessive inflammation and accelerate abscess encapsulation, ciglitazone may effectively sequester brain abscesses and limit bacterial dissemination.