bluuebunny/crossref_metadata_2025_split huggingface dataset:
HLA-G expressing Tregs inhibit bystander immune activation in HIV-1 infection (170.27)
Authors: Li Chun , Pereyra Florencia , Rychert Jenna , Rosenberg Eric , Lichterfeld Mathias , Yu Xu 
Published: January 2023

Abstract
T cells expressing the HLA class Ib molecule, HLA-G, represent an emerging non-classical population of regulatory T cells (Tregs). However, the functional role of these cells during HIV-1 infection remains unclear. Here, we performed a comprehensive investigation of HLA-G- expressing Tregs in patients with different rates of HIV-1 disease progression. Using flow cytometry, we found the proportion of HLA-G-expressing CD4 and CD8 T cells were significantly reduced in individuals with progressive HIV-1 infection (p&lt;0.001 for both CD4 and CD8 T cells). Moreover, HLA-G expressing Tregs were inversely correlated with phenotypic markers of immune activation, CD38 and HLA-DR (p=0.026 for CD4 and p&lt;0.005 for CD8 T cells), and positively correlated with CD4 T cell counts. Functional co-culture assays indicated that HLA-G-expressing CD4 and CD8 T cells were able to potently inhibit TCR-independent bystander activation, but only weakly inhibited TCR-dependent cytokine-secretion and proliferative properties of HIV-1-specific T cells. Furthermore, in vitro infection assay suggested HLA-G expressing Treg were more susceptible to HIV-1 infection (p=0.0039). These data indicate an important role of HLA-G+ Tregs for balancing bystander immune activation and anti-viral immune activity in HIV-1 infection, and suggest that the loss of these cells during advanced HIV-1 infection may contribute to immune dysregulation and HIV-1 disease progression.
The in vivo antiviral state is dependent on IFNγ (170.5)
Authors: Premenko-Lanier Mary 
Published: January 2023

Abstract
Since the discovery of interferons 50 years ago their potential therapeutic use has been a source of active research. Thus far, the most successful interferon therapy has been use of IFNα2 in combination with Ribavirin to treat Hepatitis C (HCV). The success rate for this therapy is only about a 50%. A recent case study showed that adding IFNγ to the standard IFNα/Ribavirin therapy regimen led to clearance of HCV in a patient that had failed the standard therapy. The idea that IFNγ is important for successful therapy against HCV is supported by several in vitro and in vivo studies. Using the well-established mouse model of chronic viral infection, LCMV, we have found that the natural in vivo antiviral state is dependent on interferon gamma (IFNγ). In our whole-organism model early production of IFNγ by CD8+ cells within days of a primary LCMV infection creates an antiviral environment capable of preventing secondary viral infections, whereas IFN-I signaling is surprisingly dispensable. The clearance of the secondary infection is not antigen specific since an acquired immune response to the second infection is not induced. Further, this block is transient and the mice eventually become susceptible to the secondary infection. Finally, the IFNγ induced antiviral state is effective regardless of the route of secondary viral entry. Therefore, a naturally induced sustained antiviral state is dependent on IFNγ production.
Renal Mast Cell recruitment in MRL/lpr mice (173.28)
Authors: Hernandez Sanabria Mayra , Wenderfer Scott , Ke Baozhen , Braun Michael 
Published: January 2023

Abstract
Mast cells (MC) are key effectors cells of the immune system. MC infiltration has been reported in a variety of renal diseases including lupus nephritis. Recently it has been argued that MCs are key contributors to a common pathway of progressive renal injury, however, the chemotaxic mechanism of renal MC recruitment are largely unknown. We observed a progressive age-depended MC infiltrate in kidneys of MRL/lpr mice. MRL/lpr bone marrow-derived MC (BMMC) had a high chemotatic capacity in response to MRL/lpr serum. In order to characterize the factors involved in MCs recruitment in MRL/lpr mice we performed expression array analysis in stimulated and un-stimulated MRL/lpr MCs. Serum stimulation increased BMMC expression of the integrin alpha E and chemokine receptors CCR5 and CXCR4. Kidney immunofluorescence staining confirmed these finding in situ. BMMC chemotaxis in vitro was enhanced in response to CCR5 ligands (MIP-1α and RANTES) and CXCR4 ligand (SDF-1) and was blocked by using a non-peptide chemokine receptor antagonist TAK-779. In vivo, TAK-779 significantly blocked the accumulation of renal MC in MRL/lpr mice. Our study indicate that the chemokine receptors CCR5 and CXCR4 and the integrin alpha E are important mediators of renal MC recruitment.
The role of lipid phosphate phosphatase 1 in lymphocyte egress from lymphoid organs (173.39)
Authors: Ramos-Perez Willy , Escalante-Alcalde Diana , Lynch Kevin , Schwab Susan 
Published: January 2023

Abstract
The signaling lipid sphingosine 1-phosphate (S1P) regulates vascular permeability, lymphocyte trafficking, and inflammation. The concentration of S1P is high in blood and lymph compared to lymphoid organs, and this difference guides lymphocyte exit from lymphoid organs into circulation. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. Lipid phosphate phosphatase 3 (LPP3) is essential to maintain low S1P in the thymus, and we asked whether its homolog LPP1 cooperates with LPP3 to regulate lymphoid S1P. Measurements of Lpp1 messenger RNA indicate that, like Lpp3, Lpp1 is highly expressed by thymic endothelial and epithelial cells, and lymph node (LN) lymphatic endothelial, blood endothelial, and fibroblastic reticular cells. Using mice deficient in LPP1, we have found that LPP1 is not required to maintain low S1P in thymus or LN or to enable efficient lymphocyte egress. Mice doubly deficient in LPP1 and LPP3 preliminarily have a small accumulation of mature thymocytes and minor reduction in the number of T cells in lymph compared to mice deficient in LPP3 alone, suggestive of an egress defect. Further work will test the hypothesis that LPP1 and LPP3 work together to maintain low lymphoid organ S1P and efficient lymphocyte circulation.
IL1 receptor signaling is required at multiple stages during hapten sensitization and challenge to elicit contact hypersensitivity responses (173.4)
Authors: Kish Danielle , Gorbachev Anton , Fairchild Robert 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. Elicitation of CHS is initiated when hapten-primed CD8 T cells producing IFN-γ and IL-17 stimulate endothelial cells (EC) in the challenge site to produce CXCL1, which directs required neutrophil recruitment into the challenge site. This study investigated the role of IL1 receptor signaling during hapten-specific CD8 T cell priming and in effector CD8 T cell trafficking to the challenge site to initiate the response. CHS responses were markedly lower following hapten challenge of sensitized IL1R-/- vs. wild-type (WT) mice and were associated with low CXLC1 production and neutrophil infiltration into the skin challenge site. Sensitized IL1R/- mice had marked decreases in hapten-primed CD8+ T cells producing IFN-γ or IL-17 vs. WT mice. Transferred primed WT CD8 T cells failed to induce CXCL1 to hapten skin challenge of naïve IL1R-/- mice, indicating an IL-1R requirement for CD8 T cell activation at the challenge site. Sensitized IL1R/- mice also had marked decreases in migration of hapten-presenting Langerhans cells into the skin-draining lymph nodes and transferred hapten-presenting dendritic cells from WT donors into the skin of IL-1R-/- mice failed to migrate to skin-draining lymph nodes and restore the absence of hapten-specific CD8 T cell priming. These results indicate IL-1R signaling is required during both hapten sensitization and elicitation of CHS.
‘Spin 90’ affects the Lymphocyte Recruitment and Homing to the Peritoneal Cavity (173.42)
Authors: Kim Woo-Seok , Kausar Sadia , Kang Jung-A , Lee Cho-Rong , Song Woo-Keun , Park Sung Gyoo 
Published: January 2023

Abstract
To determine the role of Spin90 in lymphocyte trafficking into the peritoneal cavity, we checked changes of the peritoneal cell population in Spin90 deficient mouse compared to the population in wild-type littermate control mouse. As a result, we found that B220+ cell population is increased in peritoneal cavity of Spin90 deficient mouse. In addition, our results showed that B220+CD23low, B220+IgMhighIgDlow B1 cells were high in Spin 90 deficient mouse as compared to wild-type littermate control. However, we found that the difference was not caused by lymphocyte developments because there were no significant differences observed in the lymphocyte population of bone marrow, thymus and peripheral lymphoid organs i.e. Spleen Lymph nodes. Our data suggest that Spin 90 could be responsible for B1 B lymphocyte migration into peritoneal cavity or into periphery from the cavity.
In vitro studies of interferon-alpha neurotoxicity (174.14)
Authors: Fritz-French Cari , Welshhans Kristy , Zhang Lynn , Bassell Gary , William Tyor 
Published: January 2023

Abstract
Elevated levels of interferon-alpha (IFNα) in the CNS is linked to cognitive dysfunction in patients with inflammatory CNS diseases such as HIV-associated dementia. Previous studies showed that IFNα treatment of neuronal cultures caused a dose dependent decrease in dendritic branching and length, mostly prevented after pre-treatment with IFNα neutralizing antibodies. To begin to evaluate the mechanism of decreased dendritic arborization, microtubule associate protein 2 (MAP2), cytoskeleton protein required for dendritic growth and stability in neurons, was looked at. IFNα was found to cause a decrease in total MAP2 protein levels in vitro as soon as 2 hrs after treatment that remained decreased through 48 hrs.. To begin to determine the signaling cascade leading up to effects on MAP2, the cell signaling pathway involving IFNα receptor (IFNAR) was evaluated to show STAT1 phosphorylation, an indicator for JAK-STAT cascade activation, peaks 2 hrs after IFNα stimulation. Both the MAPK/ERK and CREB pathways are being looked at due to their involvement in neuronal growth and STAT1 interaction. IFNα treatment appears to cause an increase ERK activity. The significance of these changese in transcription factor activity is yet to be determined. Our preliminary studies suggest that IFNα is in part acting through its receptor to reduce MAP2 expression in neurons. Determining the mechanism of IFNα neurotoxicity could lead to therapies for cognitive dysfunction during neuroinflammation.
TNF-alpha Converting Enzyme Degradates Interferon-Gamma. (174.15)
Authors: Kanzaki Hiroyuki , Chiba Mirei , Suzuki Maiko , Taubman Martin 
Published: January 2023

Abstract
Infection induced immune responses cause extensive bone destruction in periodontitis. We previously reported that TNF-alpha converting enzyme (TACE) play a role in soluble RANKL and soluble TNF-alpha cleavage from activated lymphocytes in periodontitis, and these soluble osteoclastogenic cytokines induce osteoclast activation from distant site. Interferon-gamma is known as anti-osteoclastogenic cytokine produced from activated T cells, but little is known about the post-transcriptive modification, especially in inflamed tissue. We hypothesized that TACE might modify interferon-gamma and attenuate anti-osteoclastogenic activity. Recombinant interferon-gamma is incubated with intact or heat-inactivated recombinant TACE, electrophoresed in SDS-PAGE gel, and silver stain was done. In addition, the interferon-gamma concentrations of above samples are measured with ELISA. Recombinant TACE is added into the supernatant of activated mouse splenocyte, and measured interferon-gamma concentration. Silver stain revealed that not heat-inactivated but intact recombinant TACE reduced the 16 kDa band of recombinant interferon-gamma. ELISA also showed the reduction of interferon-gamma concentration by the incubation with recombinant TACE. These data suggest that, TACE might degradate interferon-gamma and attenuate anti-osteoclastogenic activity of interferon-gamma produced from activated T cells in periodontitis.
Tyk2 signaling pathway and Mycobacterium tuberculosis (Mtb) infection (174.19)
Authors: Ray Aurelie , Fountain Jeffrey , Cooper Andrea 
Published: January 2023

Abstract
IL-12 is required for the optimal IFNg T-cell response, which is required for control of Mtb growth. IL-12R signaling is mediated by Tyrosine kinase 2 (Tyk2) which belongs to the janus kinase (JAK) family. Tyk2 phosphorylates STAT4 and STAT3, which subsequently induce transcription of target genes. We wanted to define the role of Tyk2 in IL-12R signaling during control of Mtb infection. In order to do this, we infected Tyk2 deficient mice via the aerosol route with Mtb and followed progression of the disease. We found that absence of Tyk2 resulted in a modest increase in bacterial burden associated with slightly reduced cytokine secretion (IL-17, IFNg) and T cell maturation. These data suggest Tyk2 plays a minor role in the expression of the protective response during Mtb infection. It is likely therefore that the other components of IL-12R signaling (JAK1,2 and 3) are the principal mediators of IL-12 activity in this model. These data may also reflect a role of Tyk2 in other signaling pathways such as those initiated by IL-10 and type I IFNs.
HMGB1 producing by viable cardiac fibroblasts led to myocardial contractile dysfunction via PKC-β/Erk1/2/CBP Signal Pathway (174.21)
Authors: Su Zhaoliang , Yin Jingping , Liu Yanfang , Yuan Hongyan , Zhu Haitao , Xu Huaxi 
Published: January 2023

Abstract
HMGB1 is a nuclear protein actively secreted by immune cells, cardiomyocyte, hepatocytes, pituicyte and passively released by necrotic cells. HMGB1 has been implicated in both lethality associated with endotoxemia/sepsis and cardiac contractile dysfunction. Therefore, the present work was to assess whether viable cardiac fibroblasts could release HMGB1 and whether HMGB1 could affect myocardial function. In vitro, cardiac fibroblasts were isolated and treated by LPS. HMGB1 mRNA showed no significant change during 0-12 h after stimulation with LPS, but increased significantly after 24h. Furthermore, the western blotting and immunofluorescence were also showed the same data. We found that HMGB1 active secretion might be PKC-β, Erk1/2, and CBP signal pathway. Meanwhile, we also found that collagen type I, III and osteopontin expression were increased after LPS stimulation. No evidence of inflammatory cells infiltration were noted in vivo. The type-B ultrasonic also showed that actively secreted HMGB1 by cardiac-fibroblast contributed to myocardial contractile dysfunction in sepsis. The findings of current study indicate that 1) LPS can induce HMGB1 secretion by viable cardiac fibroblasts may through PKC-β, Erk1/2, CBP signaling pathway, and 2) HMGB1 plays a role in LPS-induce myocardial contractile dysfunction. The results of the current study also have broader implications that might be more viable cells could secreted HMGB1.
IL-7-neutralizing antibody enhances in vivo IL-7 activity by interfering with normal IL-7 clearance (174.4)
Authors: Martin Chris , Surh Charles 
Published: January 2023

Abstract
Cytokine treatments are becoming increasingly popular clinical options. However, current methods of administration lack specificity and require massive doses to achieve biological effect. For IL-7 treatment, addition of a cytokine-neutralizing antibody paradoxically augments cytokine activity. This phenomenon was assumed to be due to the antibody endowing the cytokine with a longer in vivo half-life. Here we show that the durability of the antibody is indeed essential to, but not solely responsible for optimal activity of the IL-7/antibody complexes. IL-7 clearance is mediated by IL-7 receptor expressed on hematopoietic cells. Our results indicate that the neutralizing antibody perturbs receptor-mediated IL-7 degradation, thus increasing the availability of IL-7 for viable signaling events. This model is potentially applicable to many cytokines and suggests that pharmaceutical efforts intended to increase activity of a given ligand should also include measures that partially obscure the ligand from its receptor.
Chemokine-mediated Treg trafficking is required to suppress allergic airway inflammation (175.12)
Authors: Afshar Roshi , Strassner James , Seung Edward , Medoff Benjamin , Luster Andrew 
Published: January 2023

Abstract
Research has implicated a role for regulatory T cells (Tregs) in preventing asthma; however, where Tregs exert their regulatory function and the mechanisms that localize Tregs to their functional location have not been addressed. We hypothesized that chemokine receptors expressed on Tregs play an important role in directing these cells to the allergic lung and/or the reactive lymph node. We developed two murine models of allergic airway to address this hypothesis. In the sensitization model, naïve mice are injected with antigen-specific Tregs prior to immunization and aerosol challenge. In the effector model, antigen-specific Tregs are injected into mice after immunization but prior to aerosol antigen challenge. Transferred wildtype Tregs are capable of suppressing allergic airway inflammation in both models. We have found that CCR7 is required in the sensitization model and CCR4 is required in the effector model, suggesting Treg trafficking into lymph nodes is required to suppress allergic airway inflammation during the allergen sensitization phase while Treg trafficking into the lung is required to suppress allergic airway inflammation during the recall response to allergen. Using a segmental allergen challenge model in human allergic asthma subjects we further show an important role for CCR4+ Tregs in human allergic asthma. These results support our mouse data and demonstrate that CCR4 may play an important role in Treg recruitment into the allergic airways of humans.
Alternatively activated macrophage (AAM) phenotype induced in murine lungs by cockroach allergen (CRA) exposure (175.19)
Authors: Beal Dominic , Stepien David , Bouchard Jacqueline , Kim Jiyoun , Remick Daniel 
Published: January 2023

Abstract
Human studies of asthma have shown that a subset of AAM is required for disease progression. These cells differ from classically activated macrophages (mϕ) in that they produce/induce production of Th2 cytokines and are comparably inefficient in antigen presentation. In this study a murine model of CRA-induced asthma was used to study mϕ phenotypes. To induce disease, mice were immunized intra-tracheally with CRA and challenged twice 14 and 21 days later. Mice were sacrificed after the 3rd challenge and compared to naïve controls. Enzymatic digests of whole lungs were analyzed by flow cytometry, and cultured to assess cytokine production. 24 hours after the final challenge, mϕ co-stimulatory molecule expression (CD80, CD86) was reduced, as compared to both pre-challenge and age-matched naïve control mice (~40% vs 60% CD86+ cells). This effect was limited to mϕ, as CD28 and CTLA4 on T lymphocytes were unaffected. ELISA performed on supernatants of cells cultured with CRA showed enhanced levels of IL4, 5, 10, and 13 (~60, 500, 350, and 1000pg/ml respectively, vs undetectable in controls) and reduced MIP1a(~2 vs 12 ng/ml), MIP2 (~10 vs 24ng/ml), and KC (~5 vs 9ng/ml). Mϕ isolated from the spleen and peritoneal cavity showed no significant differences in surface molecule expression, indicating these effects of CRA are limited to the lungs. These data show that CRA exposure results in the generation of an AAM-like phenotype in the lung. All p values for quoted data &lt;0.05.
Tlr4-/- mice have reduced proportions of CD4+Foxp3+ Tregs in the colonic lamina propria and increased susceptibility to allergic responses to food (175.20)
Authors: Tripathi Prabhanshu , Stefka Andrew , Feehley Taylor , Pei Zhiheng , Nagler Cathryn 
Published: January 2023

Abstract
Previous work has shown that allergic responses to food are enhanced in Tlr4-/- mice. We hypothesized that allergy susceptible mice lack populations of Tregs, induced by the commensal microbiota, which are present in wild type (WT) mice. We now report that CD4+Foxp3+Tregs are significantly reduced in the colonic lamina propria (LP), but not the spleen or MLN, of Tlr4-/- mice when compared to C57Bl/6 WT mice or Tlr4+/- littermate controls. CD4+Foxp3+Tregs are also reduced in the colonic LP of mice deficient in the MyD88 or TRIF TLR4 adaptor proteins. In addition, CD4+Foxp3+Tregs isolated from Tlr4-/- mice exhibit functional deficits; their ability to produce IL-10 in response to TCR stimulation in vitro is impaired. Cluster analysis of pyrosequence derived data from fecal samples from Tlr4-/- and Tlr4+/- littermates did not segregate by genotype, suggesting that TLR4 deficiency does not itself alter the composition of the microbiome. When maintained under SPF conditions, allergen specific IgE and IgG1 elicited in response to intragastric sensitization is enhanced in Tlr4-/- mice compared to WT or Tlr4+/- controls. WT and Tlr4-/- mice that have been rederived germ free lack bacteria induced Tregs in the colonic LP; under germ free conditions both WT and Tlr4-/- mice respond robustly to sensitization with allergen. Our data suggests that increased susceptibility to allergy in Tlr4-/- mice correlates with numeric and functional impairment of bacteria-induced Foxp3+ Tregs.
Blockage of high-mobility group box 1 inhibited airway inflammation and remodeling in a murine model of chronic asthma. (175.7)
Authors: Lai Yu-ting , Lee Chen-Chen , Chang Hao-Teng 
Published: January 2023

Abstract
Damage-associated molecular patterns (DAMPs) comprise intracellular molecules characterized by the ability to reach the extracellular environment, and they involvein inflammation and cell repair. The high-mobility group box 1 (HMGB1) is a prototypic DAMP. It has two roles in microenvironment, one is DNA-binding protein and the other is cytokine. HMGB1 release during cell necrosis or apoptosis, and it’s also release by activated immune cell. Increasing HMGB1 level has been found in acute and chronic lung inflammatory conditions characterized by tissue damage and remodeling. In our study, we focus on the role of HMGB1 in chronic asthma. In a animal model of chronic asthma, mice were intraperitoneal injected with ovalbumin on day 0, 10, 20 and exposured with 5% ovalbumin five times a week for 4 weeks. After treated HMGB1 neutralization antibody 30μg/mouse by intratracheal injection three times a week for four weeks in OVA-immunized mice, HMGB1 treated mice showed decreased OVA-induced lung neutrophilia, mucus formation and collegen deposition in lung tissues by histology study and decreased lung HMGB1, HMGB1 receptors-RAGE, TLR-2 and TLR-4, collagen, MMP-9, MMP-2, pro-inflammatory cytokines- IL-17A, IL-17F, and INF-γ mRNA expression by quantitative PCR. In the future, we will investigate the further molecular mechanisms which affected by HMGB1 in lungin a chronic asthma animal model.