bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bruton's Tyrosine Kinase and Nrf2 mediate TLR-induced activation of Heme oxygenase-1 gene expression in macrophages (116.16)
Authors: Vijayan Vijith , Baumgart-Vogt Eveline , Naidu Srivatsava , Qian Guofeng , Immenschuh Stephan 
Published: January 2023

Abstract
The inducible isoform of heme oxygenase (HO)-1, is involved in heme degradation producing CO and biliverdin, mediating cytoprotection against oxidative stress. Recently, HO-1 has been shown to evoke potent anti-inflammatory and immunomodulatory effects in macrophages. Here we demonstrate that Bruton's tyrosine kinase (Btk), the gene of which is mutated in human immunodeficiency X-linked agammaglobulinemia, is involved in toll-like receptor (TLR)-induced gene expression of HO-1 in macrophages. The Btk inhibitor LFM-A13 blocked the induction of HO-1 by LPS (TLR4 ligand) in RAW264.7 macrophages and primary mouse alveolar macrophages. Furthermore, LPS-stimulated up-regulation of HO-1 gene expression was abrogated in alveolar macrophages from Btk-/- mice. In addition, inhibition of Btk with LFM-A13 attenuated the LPS-induced luciferase activity of the HO-1 promoter in transfection studies in RAW264.7 cells. This effect was mediated by the transcription factor Nrf2, which is a master regulator of the cellular antioxidant defense. Immunofluorescence studies revealed that the nuclear translocation of Nrf2 in LPS-treated macrophages was reduced by Btk inhibition. Moreover, the generation of reactive oxygen species (ROS), but not that of NO, was involved in this regulatory pathway. Btk-dependent induction of HO-1 gene expression via Nrf2 was also observed upon stimulation by TLR7 and TLR9 ligands, suggesting Btk to be generally involved in TLR-mediated HO-1 gene activation.
Enhanced interleukin-33 expression and mast cell activation in pancreas and lung tissues of pancreatic duct ligation-induced acute pancreatitis in rodents (117.16)
Authors: Kempuraj Duraisamy , Yuan Zuobiao , Theoharides Theoharis , Samuel Isaac 
Published: January 2023

Abstract
IL-33 is a newly identified member of the IL-1 cytokine family mainly expressed by epithelial cells, endothelial cells, fibroblasts, macrophages and mast cells. IL-33 release is known to increase in tissues of inflammation and is a potent activator of immune cells including mast cells. Elevation of IL-1β and TNF-α in acute pancreatitis has been already reported, and these cytokines upregulate IL-33 expression in inflammation. Activation of mast cells leads to the release of preformed mediators (eg., histamine) and proinflammatory cytokines (eg., IL-1β, TNF-α) and chemokines. Here we investigated mast cell activation and IL-33 expression following 5-48 hr of distal pancreatic duct ligation (PD)-induced acute pancreatitis in rats and mice. PD showed mast cell degranulation in the pancreas and lung, compared to sham controls. Rat plasma showed increased histamine levels with 48 hr of PD than sham controls. Immunohistochemistry, ELISA and immunoblotting results showed increased IL-33 expression in the rat and mouse exocrine pancreas and lung with 5-48 hr of PD. Murine bronchoalveolar lavage fluid showed higher IL-33 level in 48 hr of PD. Mast cell derived mediators and enhanced IL-33 expression may contribute to the progression of pancreatic and pulmonary inflammation. These results will enhance our understanding of acute pancreatitis pathogenesis and could indicate new therapeutic targets.
Chronic and acute inflammatory conditions determine MEK1 or MEK2 usage as regulators of IL-1β and sIL-1ra expression (117.18)
Authors: Burger Danielle , Carpintero Rakel , Gruaz Lyssia , Brandt Karim 
Published: January 2023

Abstract
Deregulation of the production of IL-1β and its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra), plays an important role in chronic inflammatory diseases such as multiple sclerosis. Relevant to this condition direct cellular contact with stimulated T cells potently triggers cytokine production in human monocytes. In this study we investigated the implication of MEK1 and MEK2 in the control of IL-1β and sIL-1Ra production by human monocytes upon two different stimuli: (i) soluble extracts of plasma membranes from stimulated T cells (CEsHUT), mimicking cellular contact with T cells that is relevant to chronic/sterile inflammation; and (ii) LPS that is relevant to acute/infectious inflammation. By using MEK1/2 (U0126) and MEK1 (PD98059) inhibitors and siRNA specific to MEK1 and MEK2 we demonstrate that MEK1 and MEK2 are differentially involved in the induction of IL-1β production upon chronic/sterile and acute/infectious inflammatory conditions, MEK1 being dispensable to IL-1β induction in monocytes activated by LPS but required in CEsHUT-activated monocytes. Together with the fact that immunomodulatory treatments of multiple sclerosis - IFNβ and glatiramer acetate - are using MEK2 to induce sIL-1Ra production in human monocytes, MEK1 represents a potential therapeutic target which could participate in the restoration of IL-1β/sIL-1Ra balance in chronic/sterile inflammation without affecting normal response to infectious agents.
TGF-β renders in vivo regulatory T cell function independent of TNF-α. (117.3)
Authors: Housley William , Adams Catherine , Nichols Frank , Puddington Lynn , Lingenheld Elizabeth , Zhu Li , Ragan Thiruchandurai , Clark Robert 
Published: January 2023

Abstract
TNF-α plays a multifunctional role in autoimmune diseases as reflected in the variable responses of different human diseases to anti-TNF-α therapy. Recent studies have suggested that TNF-α may modulate autoimmunity partially via effects on regulatory T cells (Tregs) mediated through the type II TNF receptor (TNFR2). We have now investigated the requirement for TNFR2 in both murine natural Treg (nTreg) and induced Treg (iTreg) suppression of autoimmunity. Surprisingly, we find that TNFR2 is required for nTreg but not iTreg suppression of colitis. Abnormal TNFR2-/- nTreg function was not associated with a decrease in accumulation, stability or phenotypic markers known to be relevant in Treg function. As iTregs are generated in the presence of TGF-β, we investigated whether activation in the presence of TGF-β could overcome the functional defect in TNFR2-/- nTregs. While pre-activation alone did not restore suppressive function of TNFR2-/- nTregs, pre-activation in the presence of TGF-β did. These results suggest for the first time that nTregs require TNF-α as a critical factor for activation, while iTregs replace this TNF-α requirement with TGF-β. Our findings thus not only expand on previous reports suggesting that nTregs are activated in sites of inflammation while iTregs are activated in lymph nodes, but also lend themselves to a new mechanistic understanding of the enigma of dichotomous responses to anti-TNF-α therapy in human autoimmune diseases.
Plasmacytoid dendritic cell depletion augments CD8 T cell IFN-γ associated atherogenic responses in a mouse model of atherosclerosis. (147.18)
Authors: Daissormont Isabelle , Christ Anette , Seijkens Tom , Sampedro Stefan , Rousch Mat , Boon Louis , Poggi Marjorie , Rademakers Timo , Halvorsen Bente , Aukrust Pal , Biessen Erik 
Published: January 2023

Abstract
Plasmacytoid dendritic cells (pDC) have been shown to play a pivotal immunogenic role in viral immune responses by releasing high IFN-alpha levels upon TLR9 activation. However, evidence is culminating that pDC also play a major role in inducing immune tolerance in chronic low grade inflammation. In this study we set out to address effects of pDC depletion on atherosclerosis development. Carotid artery lesions were induced in LDLr-/- mice by perivascular collar placement. To study effects of pDC depletion on atherogenesis, a pDC depleting antibody, 120G8, was administered daily for 4 weeks. GL113 mAb was used as isotype control. pDC depletion resulted in exacerbated atherosclerosis, characterized by an increased lesion CD3+ T cell infiltration. FACS analysis showed an increase in CD3+ T cell numbers in spleen and lymph nodes with a concurrent shift towards CD8+ T cells. This was paralleled by strongly elevated plasma IFN-γ levels. Moreover, immature but not mature pDC from spleen of atherosclerotic mice expressed increased levels of IDO and PD-L1 compared to pDC from non-atherosclerotic mice. Finally, we found that pDC isolated from human UAP/SAP patients displayed reduced IFNalpha expression, while intralesional expression of IFNalpha was unaltered at later stages of disease progression. In conclusion, our data demonstrate that immature pDC act atheroprotective by dampening CD8+ T cell responses and keeping Th2/Th1 responses in check.
TGFβ1 promotes adaptive immune response by modulating skin dendritic cell function and migration (147.24)
Authors: Mohammed Javed , Gunderson Andrew , Koubek Richard , Glick Adam 
Published: January 2023

Abstract
TGFβ1 is required for the development of Langerhans cell (LC) in the skin as TGFβ1 null mice are devoid of any LC’s. While autocrine or paracrine effects of TGFβ1 have been studied in cell-specific TGFβ1 or TGFβ1RII knockout mouse models, little information is available on effects of TGFβ1 overexpression in LC function. We overexpressed active TGFβ1 in keratinocytes and monitored the paracrine effects on skin antigen presenting cell (APC) migration in vitro and in vivo. There was an increase in migration of MHC II+CD11c+ cells from ear skin following TGFβ1 overexpression by keratinocytes and a significant increase in APC migration following treatment of mouse ear skin explant with exogenous TGFβ1. Analysis of epidermal sheets following 5 days of TGFβ1 overexpression in vivo suggested an activated phenotype of APC with loss of typical dendritic morphology and increase in MHC II staining. There was enhancement in migration of skin APC’s to the skin draining lymph nodes following application of a hapten to TGFβ1 overexpressing skin. Induction of TGFβ1 in the skin 24 hrs prior to sensitization with 0.5% Dinitro-fluorobenzene resulted in increased inflammation following challenge. These results suggest that paracrine effects of TGFβ1 promote activation and migration of skin APC’s thereby enhancing skin adaptive immune response.
Naïve T cells sense the cysteine protease allergen papain and propel basophil-mediated T helper type 2 immunity (149.13)
Authors: Liang Genqing , Xie Zhihui , Charles Nicolas , Rivera Juan , Druey Kirk 
Published: January 2023

Abstract
Sensitization to protease allergens, such as papain, or helminth infection is associated with basophil recruitment to draining lymph nodes. Basophils have the capacity to present antigen to naïve T cells and promote TH2 differentiation. How papain induces basophil migration is unknown. Here, we show that papain immunization induces production of chemokines including CCL2, CCL17 and CCL22 in lymph nodes preceding basophil accumulation. Papain-evoked basophil trafficking and TH2 differentiation were diminished by the absence of CCR2 or CCR4. Papain binds and activates antigen-inexperienced T cells directly to produce CCL17 and CCL22, and T cells appear to be the major source of chemokine following papain immunization. Papain-elicited accumulation of basophils and production of CCL17 and CCL22 in lymph nodes were abolished by T cell deficiency. These results support a previously unanticipated innate function for naïve T cells in the recognition of a cysteine protease allergen, which lies upstream of basophil-evoked TH2 effector cell development.
Eosinophils regulate dendritic cell-induced Th2 polarization following allergen challenge in a mouse model of asthma (151.10)
Authors: Jacobsen Elizabeth , Zellner Katie , Colbert Dana , Lee Nancy , Lee James 
Published: January 2023

Abstract
Eosinophil recruitment and accumulation in the lungs of asthmatics is a hallmark feature of asthma. The causative relationship between eosinophils and induced Th2 pulmonary pathologies remains unclear. Our data suggest a novel role for eosinophils as immune modulators that drive Th2-mediated pulmonary pathologies through modulation of dendritic cell function leading to the suppression of Th1/Th17 immune responses. Methods: Eosinophils and ovalbumin (OVA)-pulsed myeloid dendritic cells were adoptively transferred into IL-5-/- (eosinophil-low) or PHIL mice (eosinophil-null) at the time of allergen challenge using an established acute OVA protocol. Allergen-induced pulmonary changes were assessed as changes in lung and lung draining lymph node (LDLN) cells, activation/polarization of T cells, and induced lung histopathologies. Conclusions: We demonstrate that a threshold level of eosinophils must migrate to the lung draining lymph node to promote dendritic cell recruitment and thus activation of antigen-specific memory T cells. Expression of MHC II or CCR7 on eosinophils is not necessary for proliferation of T cells in the LDLN. These lymphatic eosinophils are necessary to suppress Th1/Th17 neutrophilic polarized immune responses initiated by OVA-pulsed dendritic cells during allergen challenge. These results imply an important function for eosinophils in modulating the balance between Th2 and Th1/Th17 pathways in the development of allergic respiratory inflammation.
Fullerene derivatives as a novel approach to controlling asthma via induction of the dual-specificity Phophatase-1 gene in mast cells (151.8)
Authors: Dellinger Anthony , Zhou Zhiguo , MacFarland Darren , Kepley Christopher 
Published: January 2023

Abstract
Fullerenes are a class of novel carbon allotropes being investigated potential therapeutic agents; here we report a biological function for C70-based fullerenes derivatized with inositol (C70-I). Human Mast Cells (MC) were harvested from tissue and incubated with C70-based fullerenes derivatives. Next, mediator release (cytokine and beta-hexosamindase) or protein levels (Western blot or immunoprecipitation) was measured. This derivative induced significant increases in the gene and protein expression of human mast cell dual-specificity phosphate one (DUSP1); master regulator of the corticosteroid response in asthma. This increase in FCϵRI-induced DUSP1 expression resulted in the dephosphorylation of mitogen-activated protein kinases and acted synergistically with corticosteroids to diminish mediator release from MC. The increase in DUSP1 protein expression was due in part on the ability of C70-I to prevent the ubiquitination and degradation of DUSP1. These findings identify yet another potential application of functionalized fullerenes as a way to increase the efficacy of corticosteroids or use as an anti-inflammatory through the control of DUSP1.
Two distinct Th9 subpopulations are generated by activating naïve CD4 cells with either antigen/APC, or anti-CD3/CD28 antibodies (152.12)
Authors: Tan Cuiyan , Vistica Barbara , Nugent Lindsey , Zureick Andrew , Shi Guangpu , Gery Igal 
Published: January 2023

Abstract
Recent studies identified and partially characterized the Th9 lineage, using anti- CD3/CD28 Abs for activation during polarization. Using TCR transgenic mice we showed, however, that Th9 are also generated by activation with the specific Ag, hen egg lysozyme (HEL) (J. Imm., 185:6795, 2010). Here, we compared Th9 lines generated by either HEL, or anti-CD3/CD28 Abs, but similarly polarized by IL-4/TGF-β. Main observations: (i) IL-9 and IL-10 are similarly secreted in the supernatant by HEL or Ab-activated cultures. Intracellular IL-9 is expressed earlier in the Ab-activated cells, but IL-10 is similarly produced by the two subsets. (ii) Both subsets induced ocular inflammation when adoptively transferred into mice expressing HEL in their eyes, but pathogenicity of Ag-stimulated Th9 was restricted to day 3 in culture, whereas Ab-stimulated Th9 induced disease when collected after 3-5 days in culture. (iii) The two Th9 subsets expressed similarly the majority of tested major surface Ags, but differed in expression of CD45RB, CD69, α4β7 and αEβ7. (iv) The two Th9 subsets differed remarkably in their expression of several chemokine and chemokine receptor transcripts, with patterns strikingly similar to those reported for the two Th17 subsets. Thus, different modes of activation of naïve CD4 cells during polarization yield two distinct subpopulations of Th9.
The expression of the abundant secondary granule proteins MBP-1 and EPO is required for the maturation of eosinophil-lineage committed progenitor cells in the hematopoietic compartments of mice (153.27)
Authors: Doyle Alfred , Jacobsen Elizabeth , Ochkur Sergei , McGarry Michael , Shim Kevin , Nguyen David , Protheroe Cheryl , Colbert Dana , Dyer Kimberly , Rosenberg Helene , Lee Nancy , Lee James 
Published: January 2023

Abstract
Eosinophil effector functions have been hypothesized to be mediated in part by the release of proteins stored in the secondary granules of mature cells of this leukocyte lineage. Major basic protein-1 (MBP-1) and eosinophil peroxidase (EPO) comprise the majority of protein in these granules. No role has been speculated for these proteins in eosinophilopoiesis and/or the accumulation of mature cells in circulation. Methods: Eosinophilopoiesis and eosinophil accumulation in the periphery were assessed in single and double knockout (MBP-1-/- and/or EPO-/-) mice. Bone marrow and peripheral blood leukocytes were assessed by IHC, FACS and in vitro cell culture assays. Mice were subjected to an acute OVA protocol assessing induced pulmonary pathologies in each of the strains of granule protein knockout mice. Results: We demonstrate that, unlike the single deficiency of MBP-1 or EPO, the absence of both granule proteins resulted in the loss of peripheral blood eosinophils. IHC assessments of bone marrow and spleen demonstrate that eosinophil lineage commitment occurs in these mice. However, these assessments and FACS studies demonstrated a blockade in the maturation of eosinophil-lineage committed cells. This blockade is not rescued by ex vivo culture or by bone marrow engraftment into wild type recipient mice. Similar to other eosinophil-less mouse models, MBP-1-/-/EPO-/- mice also fail to develop pulmonary inflammation in an OVA protocol.
Id3 is a critical regulator of γδ-T cell development (153.41)
Authors: Lee Sang Yun , Zuniga-Pflucker Juan-Carlos , Wiest David 
Published: January 2023

Abstract
αβ and γδ T cells are thought to arise from a common precursor during development in the thymus. Previously, we have shown that αβ/γδ lineage choice is dictated by differences in T cell receptor (TCR) signal strength defined by differential activation of the ERK-Egr-Id3 pathway. In particular, we found that Id3 is required for strong TCR signals to both promote adoption of the γδ-fate and oppose the αβ-fate outcome. Importantly, the effects of Id3-deficiency on γδ T cell development differ depending on the γδ subset. While Id3-deficiency impairs the development of the Vγ2-expressing and Vγ3 dendritic epidermal T cell (DETC) subsets, it results in the dramatic expansion of Vγ1.1Vδ6.3 T cells which are thought to be innate type NK γδ T cells. Fetal thymic organ culture analysis indicates that Id3-deficiency blocks DETC development by interfering with selection in the thymus, not by blocking expression of the canonical DETC TCR complex. Conversely, single-cell PCR analysis has revealed that the junctional diversity of CDR3s of the Vγ1.1Vδ6.3 expressing cells that are expanded in Id3-deficient mice exhibit evidence of ligand-mediated selection. These results are consistent with the notion that development of these cells is normally restricted by ligand-engagement, but this restriction is disabled in the absence of Id3. Altogether, these results indicate that Id3 plays a critical role not only in regulating fate selection, but also in shaping the γδ TCR repertoire.
Immunisation analysis and animal protection experiments of a recombinant multi-epitope assembly peptide from Herpes Simplex Virus Type 2 (155.35)
Authors: Yuexi Li , Xingsheng Wang , Guangyan Xie , Jianming Liao , Dengke Yin , Wenyan Guan , Mingjie Pan , Jingnian Li 
Published: January 2023

Abstract
Human herpes simplex virus 2 (HSV2) has been the main cause for genital herpes, causes a significant health problem worldwide, and no effective vaccine is available. Multi-epitope assembly peptides vaccination is a promising mean to achieve protective immunity and to avoid immunopathology. A recombinant Multi-Epitope Assembly Peptide (MEAP) including 12 antigen epitopies from HSV2 was expressed and purified by genetic engineering, its immunity and protection efficacy against HSV2 infection were identified in mice. The twelve epitopies contained six B cell epitopies from six envelope glycoproteins, B, C, D, E, G and I of HSV2 respectively, four CD4+ T cell epitopes from B and D, and two CD8+ T cell epitopes from D. they are responsible for the elicitation of the neutralizing antibodies and CTLs that impart protective immunity to the host. all above epitopes were inserted into the extracellular fragment of HSV-2 glycoprotein D to construct multi-epitope assembly peptides by replacing some non-epitope amino acid sequences. The MEAP could elicit high titer neutralizing antibodies and cell-mediated immune responses in mice and rabbits. The mice immunized with the MEAP were completely protected against HSV-2 infection death at a lethal dose, and the virus shedding, inflammation severity in the mice were reduced significantly compared with the control mice, which indicates that it might be a potential candidate vaccine.
A novel HER-2-specific exosome-targeted T cell-based vaccine: immunotherapy of established lung metastasis in transgenic HLA-A2/HER-2 mice (155.37)
Authors: Wang Lu , Xie Yufeng , Wei Yangdou , Mulligan Sean , Xiang Jim 
Published: January 2023

Abstract
CD4+ T cell vaccine has less been studied. In this study, we demonstrated that active CD4+ T (aT) cells with uptake of ovalbumin (OVA)-pulsed dendritic cell (DCova)-derived exosome (EXOova) express exosomal peptide/major histocompetibility complex (pMHC) I and costimulatory molecules. EXOova-uptaken (targeted) CD4+ aT (aTexo) cells can stimulate central memory CD8+ cytotoxic T lymphocyte (CTL) responses, more efficient in vivo antitumor immunity and long-term CD8+ T cell memory responses than DCova, and break the self immune tolerance in two transgenic mouse models leading to OVA- and neu-specific CTL-mediated diabetes and antitumor, respectively. We further elucidated that aTEXO’s stimulatory effect is mediated via its IL-2 secretion and acquired CD80 costimulation, and specifically targeted to CD8+ T cells in vivo via acquired pMHC I complexes. Therefore, EXO-targeted CD4+ T cell vaccine may represent a novel and highly effective vaccine strategy for inducing immune responses against not only tumors, but also other infectious diseases. Therefore, EXO-targeted CD4+ T cell vaccine may represent a novel effective vaccine strategy for therapeutic treatment of patients with early stage of HER-2-positive or trastuzumab-resistant HER-2-positive breast cancers, and for adjuvant treatment of patients with potential risk of metastasis after surgical treatment.