bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophils Exhibit Differential Requirements for Homing Molecules in Their Lymphatic and Blood Trafficking into Draining Lymph Nodes
Authors: Gorlino Carolina V. , Ranocchia Romina P. , Harman María F. , García Iris A. , Crespo María I. , Morón Gabriel , Maletto Belkys A. , Pistoresi-Palencia María C. 
Published: July 2014

Abstract
Although much is described about the molecules involved in neutrophil migration from circulation into tissues, less is known about the molecular mechanisms that regulate neutrophil entry into lymph nodes (LNs) draining a local inflammatory site. In this study, we investigated neutrophil migration toward LNs in a context of inflammation induced by immunization of BALB/c mice with OVA emulsified in CFA. We demonstrated that neutrophils can enter LNs of OVA/CFA-immunized mice not only via lymphatic vessels but also from blood, across high endothelial venules. By adoptive transfer experiments, we showed that this influx was dependent on an inflammatory-state condition and previous neutrophil stimulation with OVA/anti-OVA immune complexes. Importantly, we have demonstrated that, in the migratory pattern to LNs, neutrophils used L-selectin and P-selectin glycoprotein ligand-1, macrophage-1 Ag and LFA-1 integrins, and CXCR4 to get access across high endothelial venules, whereas macrophage-1 Ag, LFA-1, and CXCR4 were involved in their trafficking through afferent lymphatics. Strikingly, we found that stimulation with immune complexes significantly upregulated the expression of sphingosine-1-phosphate receptor 4 on neutrophils, and that treatment with the sphingosine-1-phosphate agonist FTY720 altered neutrophil LN-homing ability. These findings summarized in this article disclose the molecular pattern that controls neutrophil recruitment to LNs.
Macrophage PTEN Regulates Expression and Secretion of Arginase I Modulating Innate and Adaptive Immune Responses
Authors: Sahin Emine , Haubenwallner Stefan , Kuttke Mario , Kollmann Isabella , Halfmann Angela , Dohnal Alexander B. , Chen Li , Cheng Paul , Hoesel Bastian , Einwallner Elisa , Brunner Julia , Kral Julia B. , Schrottmaier Waltraud C. , Thell Kathrin , Saferding Victoria , Blüml Stephan , Schabbauer Gernot 
Published: July 2014

AbstractThe activation of innate immune cells triggers numerous intracellular signaling pathways, which require tight control to mount an adequate immune response. The PI3K signaling pathway is intricately involved in innate immunity, and its activation dampens the expression and release of proinflammatory cytokines in myeloid cells. These signaling processes are strictly regulated by the PI3K antagonist, the lipid phosphatase, PTEN, a known tumor suppressor. Importantly, PTEN is responsible for the elevated production of cytokines such as IL-6 in response to TLR agonists, and deletion of PTEN results in diminished inflammatory responses. However, the mechanisms by which PI3K negatively regulates TLR signaling are only partially resolved. We observed that Arginase I expression and secretion were markedly induced by PTEN deletion, suggesting PTEN−/− macrophages were alternatively activated. This was mediated by increased expression and activation of the transcription factors C/EBPβ and STAT3. Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity.
IL-2 Induction of Blimp-1 Is a Key In Vivo Signal for CD8+ Short-Lived Effector T Cell Differentiation
Authors: Boulet Salix , Daudelin Jean-François , Labrecque Nathalie 
Published: July 2014

Abstract
During infection or vaccination, only a small proportion of CD8+ T cells differentiate into memory cells. The mechanisms underlying the differentiation of CD8+ T cells into short-lived effector cells (SLECs) or memory precursor effector cells are poorly defined. It was recently shown in infectious models that the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp-1) enhances the formation of SLECs. The factors controlling Blimp-1 expression leading to the in vivo formation of SLECs are still not known. However, it has been shown that cytokines such as IL-2 induce Blimp-1 expression in vitro. In this study, we took advantage of the low-inflammation model of dendritic cell immunization to study the role of the IL-2/Blimp-1 axis in SLEC differentiation as well as the importance of Blimp-1 expression in memory precursor effector cells for proper CD8+ memory generation. Our results show that Blimp-1 deficiency affects effector differentiation and function in the absence of inflammation. Unexpectedly, memory generation was not affected in Blimp-1–deficient OT-I cells responding to vaccination. In addition, modulation of the bioavailability of IL-2 by injection either of a blocking Ab or of the cytokine, demonstrates a link between IL-2, Blimp-1 induction, and SLEC formation in wild-type cells. Conversely, injection of IL-2 had less effect on Blimp-1–deficient CD8+ T cells, indicating that the effect of IL-2 on in vivo SLEC differentiation is mediated by Blimp-1. In conclusion, IL-2 induction of Blimp-1 expression is a key regulator of SLEC differentiation in vivo.
NK Cells Are the Crucial Antitumor Mediators When STAT3-Mediated Immunosuppression Is Blocked in Hepatocellular Carcinoma
Authors: Sui Qiangjun , Zhang Jian , Sun Xiaoxia , Zhang Cai , Han Qiuju , Tian Zhigang 
Published: July 2014

Abstract
STAT3 is highly activated in a wide variety of cancers and functions to promote tumor survival. We previously reported that blocking STAT3 activation inhibited human hepatocellular carcinoma (HCC) growth in vitro, but whether this treatment also triggered antitumor immune responses in vivo remained unknown. In this study, we found that blocking the STAT3 pathway in HCC cells dramatically inhibited murine HCC growth in vivo and prolonged survival of tumor-bearing mice. Importantly, the presence of STAT3-blocked HCC augmented NK cell cytotoxicity against HCC and increased expression of molecules associated with NK cell activation and cytotoxicity. In T cell–deficient nude mice, a unique NK cell–mediated antitumor function against STAT3-blocked HCC was suggested. NK cells were shown to be necessary and sufficient in NK or T cell depletion experiments, or by adoptively transferring NK cells. Furthermore, regulatory T cells and immunosuppressive IL-10 and TGF-β cytokines were reduced in mice bearing STAT3-blocked HCC cells, suggesting that these factors may be involved in HCC-induced NK cell suppression. These findings indicate that blocking STAT3 in HCC cells can initiate innate immunity in vivo.
TRIL Is Involved in Cytokine Production in the Brain following Escherichia coli Infection
Authors: Wochal Paulina , Rathinam Vijay A. K. , Dunne Aisling , Carlson Thaddeus , Kuang Wen , Seidl Katherine J. , Hall J. Perry , Lin Lih-Ling , Collins Mary , Schattgen Stefan A. , MacKay Christopher R. , Fagundes Caio T. , Carpenter Susan , Fitzgerald Katherine A. , O’Neill Luke A. J. 
Published: July 2014

Abstract
TLR4 interactor with leucine-rich repeats (TRIL) is a brain-enriched accessory protein that is important in TLR3 and TLR4 signaling. In this study, we generated Tril−/− mice and examined TLR responses in vitro and in vivo. We found a role for TRIL in both TLR4 and TLR3 signaling in mixed glial cells, consistent with the high level of expression of TRIL in these cells. We also found that TRIL is a modulator of the innate immune response to LPS challenge and Escherichia coli infection in vivo. Tril−/− mice produce lower levels of multiple proinflammatory cytokines and chemokines specifically within the brain after E. coli and LPS challenge. Collectively, these data uncover TRIL as a mediator of innate immune responses within the brain, where it enhances neuronal cytokine responses to infection.
Does β-Hexosaminidase Function Only as a Degranulation Indicator in Mast Cells? The Primary Role of β-Hexosaminidase in Mast Cell Granules
Authors: Fukuishi Nobuyuki , Murakami Shinya , Ohno Akane , Yamanaka Naoya , Matsui Nobuaki , Fukutsuji Kenji , Yamada Sakuo , Itoh Kouji , Akagi Masaaki 
Published: July 2014

Abstract
β-Hexosaminidase, which is generally present in the lysosome, is essential for glycoprotein metabolism in the maintenance of cell homeostasis. In mast cells (MCs), large amounts of β-hexosaminidase are present in the granules as opposed to the lysosome, and the biological role of MC β-hexosaminidase has yet to be fully elucidated. Therefore, we investigated the biological role of β-hexosaminidase in MC granules. Bone marrow-derived MCs from C57BL/6 (BL/6-BMMC) or β-hexosaminidase gene–deficient (hexb−/−-BMMC) mice were transplanted into MC-deficient (WBB6F1/J-KitW/KitW-v [W/Wv]) mice to generate MC-reconstituted models. In asthma model experiments, no differences were observed in the symptoms of BL/6, W/Wv, BL/6-BMMC–reconstituted W/Wv, or hexb−/−-BMMC–reconstituted W/Wv mice. In Staphylococcus epidermidis experimental infection model experiments, the severity of symptoms and frequency of death were markedly higher in W/Wv and hexb−/−-BMMC–reconstituted W/Wv mice than in BL/6 and BL/6-BMMC–reconstituted W/Wv mice. The growth of S. epidermidis in an in vitro study was clearly inhibited by addition of BL/6-BMMC lysate, but not by addition of hexb−/−-BMMC lysate. Moreover, suppression of bacterial proliferation was completely recovered when bacteria were incubated with hexb−/−-BMMC lysate plus β-hexosaminidase. Transmission electron microscopy indicated that the cell wall of S. epidermidis was heavily degraded following coincubation of bacteria with BL/6-BMMC lysate, but not following coincubation with hexb−/−-BMMC lysate. These findings strongly suggest that MC granule β-hexosaminidase is crucial for defense against bacterial invasion, but is not involved in the allergic response. Our results also suggest that the bactericidal mechanism of β-hexosaminidase involves degradation of bacterial cell wall peptidoglycan.
Leukocyte β7 Integrin Targeted by Krüppel-like Factors
Authors: Alles Melanie , Turchinovich Gleb , Zhang Pumin , Schuh Wolfgang , Agenès Fabien , Kirberg Jörg 
Published: July 2014

AbstractConstitutive expression of Krüppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin β7 (Itgb7, Ly69) by binding to the β7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the β7 promoter, indicating that these factors may compete for target sequence(s). Whereas β7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because β7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when β7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer’s patches, much like β7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of β7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of β7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression.
Differential Role for p120-Catenin in Regulation of TLR4 Signaling in Macrophages
Authors: Yang Zhiyong , Sun Dong , Yan Zhibo , Reynolds Albert B. , Christman John W. , Minshall Richard D. , Malik Asrar B. , Zhang Yang , Hu Guochang 
Published: July 2014

Abstract
Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow–derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain–containing adapter-inducing IFN-β–dependent IFN regulatory factor 3 activation and release of IFN-β upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4–TIR domain–containing adapter-inducing IFN-β signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.
IL-33 and Thymic Stromal Lymphopoietin Mediate Immune Pathology in Response to Chronic Airborne Allergen Exposure
Authors: Iijima Koji , Kobayashi Takao , Hara Kenichiro , Kephart Gail M. , Ziegler Steven F. , McKenzie Andrew N. , Kita Hirohito 
Published: July 2014

Abstract
Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. In this study, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naive mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 wk. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE Ab production, type 2 cytokine response, and airway hyperresponsiveness in 4 wk, followed by airway remodeling in 8 wk. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells was observed. CD4+ T cells and type 2 innate lymphoid cells contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33R (Il1rl1−/−) and thymic stromal lymphopoietin receptor (Tslpr−/−) showed significant reduction in airway inflammation, IgE Ab levels, and airway hyperresponsiveness. In contrast, mice deficient in IL-25R or IL-1R showed minimal differences as compared with wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and thymic stromal lymphopoietin most likely play key roles in this process.
Activation of Rheumatoid Factor–Specific B Cells Is Antigen Dependent and Occurs Preferentially Outside of Germinal Centers in the Lupus-Prone NZM2410 Mouse Model
Authors: Sang Allison , Niu Haitao , Cullen Jaime , Choi Seung Chul , Zheng Ying Yi , Wang Haowei , Shlomchik Mark J. , Morel Laurence 
Published: July 2014

Abstract
AM14 rheumatoid factor (RF) B cells in the MRL/lpr mice are activated by dual BCR and TLR7/9 ligation and differentiate into plasmablasts via an extrafollicular (EF) route. It was not known whether this mechanism of activation of RF B cells applied to other lupus-prone mouse models. We investigated the mechanisms by which RF B cells break tolerance in the NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) strain in comparison with C57BL/6 (B6) controls, each expressing the AM14 H chain transgene in the presence or absence of the IgG2aa autoantigen. The TC, but not B6, genetic background promotes the differentiation of RF B cells into Ab-forming cells (AFCs) in the presence of the autoantigen. Activated RF B cells preferentially differentiated into plasmablasts in EF zones. Contrary to the MRL/lpr strain, TC RF B cells were also located within germinal centers, but only the formation of EF foci was positively correlated with the production of RF AFCs. Immunization of young TC.AM14 H chain transgenic mice with IgG2aa anti-chromatin immune complexes (ICs) activated RF B cells in a BCR- and TLR9-dependent manner. However, these IC immunizations did not result in the production of RF AFCs. These results show that RF B cells break tolerance with the same general mechanisms in the TC and the MRL/lpr lupus-prone genetic backgrounds, namely the dual activation of the BCR and TLR9 pathways. There are also distinct differences, such as the presence of RF B cells in GCs and the requirement of chronic IgG2aa anti-chromatin ICs for full differentiation of RF AFCs.
Inhibition of the Classical Pathway of Complement by Meningococcal Capsular Polysaccharides
Authors: Agarwal Sarika , Vasudhev Shreekant , DeOliveira Rosane B. , Ram Sanjay 
Published: July 2014

Abstract
Almost all invasive Neisseria meningitidis isolates express capsular polysaccharide. Ab is required for complement-dependent killing of meningococci. Although alternative pathway evasion has received considerable attention, little is known about classical pathway (CP) inhibition by meningococci, which forms the basis of this study. We engineered capsulated and unencapsulated isogenic mutant strains of groups A, B, C, W, and Y meningococci to express similar amounts of the same factor H–binding protein (fHbp; a key component of group B meningococcal vaccines) molecule. Despite similar anti-fHbp mAb binding, significantly less C4b was deposited on all five encapsulated mutants compared with their unencapsulated counterparts (p &lt; 0.01) when purified C1 and C4 were used to deposit C4b. Reduced C4b deposition was the result of capsule-mediated inhibition of C1q engagement by Ab. C4b deposition correlated linearly with C1q engagement by anti-fHbp. Whereas B, C, W, and Y capsules limited CP-mediated killing by anti-fHbp, the unencapsulated group A mutant paradoxically was more resistant than its encapsulated counterpart. Strains varied considerably in their susceptibility to anti-fHbp and complement despite similar Ab binding, which may have implications for the activity of fHbp-based vaccines. Capsule also limited C4b deposition by anti–porin A mAbs. Capsule expression decreased binding of an anti-lipooligosaccharide IgM mAb (∼1.2- to 2-fold reduction in fluorescence). Akin to observations with IgG, capsule also decreased IgM-mediated C4b deposition when IgM binding to the mutant strain pairs was normalized. In conclusion, we show that capsular polysaccharide, a critical meningococcal virulence factor, inhibits the CP of complement.
γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance
Authors: Kong Xiaohui , Sun Rui , Chen Yongyan , Wei Haiming , Tian Zhigang 
Published: July 2014

Abstract
The mechanisms of liver hepatitis B virus (HBV)–induced systemic immune tolerance are still elusive, and the role of γδT cells has not yet been described. We examined the function of γδT cells in HBV-carrier mice––immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that γδT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8+ T cells. Of interest, IL-17−/− mice phenocopied TCRδ−/− mice in terms of losing HBV persistence, and adoptive transfer of γδT cells restored HBV-persistent expression in TCRδ−/− mice. We further observed that hepatic CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRδ−/− and IL-17−/− mice. MDSC numbers also recovered after adoptive transfer of γδT cells, particularly Vγ4+ T cells. Furthermore, anti-Gr1–mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to γδT cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8+ T cells and promoted HBV clearance. We also observed enhanced CD8+ T cell number with a notable decline of MDSCs in TCRδ−/− mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRδ−/− mice not only exhibited increased anti-HBV CD8+ T cells but also markedly reduced MDSCs. Overall, the current study reveals that γδT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8+ T cell exhaustion.
Platelet Activation and Apoptosis Modulate Monocyte Inflammatory Responses in Dengue
Authors: Hottz Eugenio D. , Medeiros-de-Moraes Isabel M. , Vieira-de-Abreu Adriana , de Assis Edson F. , Vals-de-Souza Rogério , Castro-Faria-Neto Hugo C. , Weyrich Andrew S. , Zimmerman Guy A. , Bozza Fernando A. , Bozza Patrícia T. 
Published: July 2014

Abstract
Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations, from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet–monocyte interactions to inflammatory responses in dengue have not been addressed. Patients with dengue were investigated for platelet–monocyte aggregate formation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. We observed increased levels of platelet–monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1β, IL-8, IL-10 and MCP-1, whereas exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet–monocyte aggregates. Moreover, IL-10 secretion required platelet–monocyte contact but not phagocytosis. Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue.