bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heparan sulfate-induced pancreatic inflammatory response is TLR4 dependent (162.2)
Authors: Akbarshahi Hamid , Axelsson Jakob , Said Katarzyna , Fischer Hans , Malmström Anders , Andersson Roland 
Published: January 2023

Abstract
Degraded extracellular matrix can stimulate the innate immune system via the Toll-Like Receptor-4 (TLR4). In the pancreas, heparan sulfate (HS) on syndecan anchored in the ductal epithelium, can be cleaved off by enzymes and potentially activate TLR4 signalling. To investigate these signalling events, we infused heparan sulfate (HS) into the pancreatic duct of the mice. Phosphate-buffered saline and lipopolysaccharide (LPS)were used as controls. The wild type C57BL/6J mice were sacrificed after 1, 3, 6, 9, and 48 hours. To study the downstream TLR4 signalling pathway of HS in the pancreas, genetically engineered mice lacking TLR4, MyD88 or IRF3 were used. Neutrophil sequestration and myeloperoxidase activity in the pancreas were increased 9 hours following HS challenge. However, in TLR4, MyD88, and IRF3 knockout mice the neutrophil recruitment and myeloperoxidase activity were abrogated in the HS group while the LPS response was only abolished in TLR4 and MyD88 knockouts. In wild type mice, the monocyte chemoattractant protein -1 increased at 3 hours after infusion while RANTES increased after 9 hours. In conclusion, we have shown that HS is capable of initiating an innate immune response in the pancreas distinctly different from that induced by LPS. Furthermore, the data shows that the inflammatory response is TLR4 dependent and mediated through both MyD88-dependent and independent pathways. Thus, heparan sulfate is potentially involved in the ductal defense in the pancreas.
Cannabinoids Receptor-2 (CB2) agonist ameliorates spontaneous colitis by attenuating neutrophils, mast cells, natural killer cells and inducing endogenous cannabinoids (162.3)
Authors: Singh Udai , Singh Narendra , Singh Balwan , Price Robert , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines and an influx of neutrophils. It is well known that endocannabinoids mediate protection against intestinal inflammation. Here, we investigate the activation of endocannabinoid receptors -2 (CB2) by JWH-133, a potent CB2 agonist- mediated inhibition of chronic colitis in IL-10-/- mice. In the present study, we report that JWH-133 effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis including the decrease in body weight, and increased the expression of endocannabinoid-2 receptors in the colon. After JWH-133 treatment, the percentage of CD4+ T cells in the spleen of colitis mice was restored to normal levels and there was a decrease in these cells in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN). Similarly, the percentage of mast, natural killer (NK1.1) and activated T cells in the LP of colitis mice declined after JWH-133 treatment. JWH-133 also reduced the number and percentage of neutrophils that were induced during chronic colitis progression. These findings suggest that JWH-133 ameliorates chronic colitis by inducing endogenous CB2 receptors at sites of inflammation and reduces Th1-, mast-, NK1.1 cells, and neutrophils from the spleen and LP. These results support the idea that the CB2 receptor agonist may be developed as a novel therapeutic target for IBD.
IL-25 enhances the accumulation and function of lung resident TH2 memory/effector cells during allergic inflammation (163.14)
Authors: Liu Bo , Chen Chun-Yu , Ohta Shoichiro , Angkasekwinai Pornpimon , Burwinkel Karen , Izuhara Kenji , Liu Yong-Jun , Wang Yui-Hsi 
Published: January 2023

Abstract
IL-25 is a TH2-promoting cytokine, however, its role in regulating the maintenance and function of TH2 memory/effector cells in vivo remains elusive. We have developed a novel mouse model to study the regulation of TH2 memory/effector cells after re-exposure to OVA antigen. Phenotypic analyses reveal that the recalled TH2 memory/effector cells in lung express distinct level of IL-25 receptor (IL-25R), ST2, and OX40. Notably, the frequency of local IL-25R+CD4+ TH2 memory/effector cells in inflamed lung, but not other lymphoid tissues, is elevated after increased numbers of OVA antigen re-exposure. These lung resident IL-25R+CD4+ TH2 memory/effector cells are much more potent to produce TH2 cytokines than the TH2 cells in other lymphoid tissues. Enforced expression of IL-25R by T cells in mice resulted in increased accumulation of local antigen-specific TH2 memory/effector cells, leading to more prominent airway inflammation, compare to those of littermate controls in our novel mouse model of allergic lung diseases. These results suggest that IL-25 may promote allergic inflammation by enhancing the accumulation and function of lung resident IL-25R+CD4+ TH2 memory/effector cells in vivo.
Skin histopathology, including a significant itch response, associated chemically-induced contact hypersensitivity reactions in the mouse are, in part, a consequence of skin infiltrating eosinophils (163.16)
Authors: Condjella Rachel , Protheroe Cheryl , Ochkur Sergei , Zellner Katie , Colbert Dana , Scott Gregory , Jacoby David , Fryer Allison , Lee Nancy , Lee James 
Published: January 2023

Abstract
Atopic dermatitis and allergic contact dermatitis are two of the most common skin diseases. In both diseases, eosinophils have been suggested as potential contributors of the pathologies linked with these skin conditions. Our goal was to establish a causative relationship between the inflammatory response of chemically induced contact hypersensitivity and eosinophil-mediated activities. Wild type and eosinophil-less PHIL mice were sensitized and challenged with 2,4-dinitrochlorobenzene (DNFB) or alternatively trimellitic anhydride (TMA). Time lapsed videography was used to capture the number of itching events associated with treatment. Immunohistochemistry for eosinophils and nerves was performed to correlate the effect of dermatitis on innervation and eosinophil accumulation in these mice. Our studies showed that in both the DNFB and TMA models a robust eosinophil infiltrate occurred that was accompanied by copious levels of eosinophil degranulation. More importantly, these studies demonstrated that metrics of inflammation (e.g., induced ear swelling (i.e., thickness)) was reduced in PHIL mice relative to wild type. Our observations were also directly correlative with a loss of nerve growth and branching in PHIL mice. These data implicate eosinophils as contributors to the pathologies linked with chemically-induced contact hypersensitivity, including the induced itch responses associated with these models.
Opposing roles for fyn and lyn kinases in FcγR signaling and IgG-mediated systemic anaphylaxis (163.17)
Authors: Falanga Yves , Finkelman Fred , Odom Sandra , Rivera Juan , Oskeritzian Carole , Ryan John 
Published: January 2023

Abstract
Mast cells (MCs) are key players in the innate immune system and atopic diseases. Once activated, they degranulate and produce cytokines, resulting in the recruitment of other immune cells and the clearance of the infectious agent. In this study we focused on MC activation via the immunoglobulin G (IgG) receptors, FcγR. We found that croslinkage of mouse mast cells with an antibody recognizing the low affinity receptors FcγRIIb and FcγRIII induced tyrosine phosphorylation of both Lyn and Fyn. We used Fyn- or Lyn-deficient (KO) mice to demonstrate that FcγR, like the IgE receptor, FcϵRI, triggers mast cell degranulation and cytokine release via a Fyn- and Lyn-dependent manner. Lyn KO mast cells displayed increased FcγR-mediated degranulation and cytokine release, while a decrease was observed using Fyn KO MC. We show that the role for Fyn and Lyn downstream of FcγR is not restricted to the MC lineage, as similar effects were found in basophils and macrophages. Furthermore, these effects were consistent in vivo, when measuring IgG-mediated passive systemic anaphylaxis (PSA). Collectively, these data demonstrate Fyn and Lyn activation during FcγR signaling and highlight their homeostatic contribution to IgG-mediated inflammation.
Walnut extract induces near-fatal anaphylactoid shock via the complement C3 dependent pathway in naïve mice (163.2)
Authors: Gangur Venu , Parvataneni Sitaram , Gonipeta Babu 
Published: January 2023

Abstract
Walnut is a major tree nut associated with severe allergic/anaphylactic reactions in humans. Here we surprisingly found that oral administration of walnut extract to naïve mice resulted in a sharp drop in rectal temperature associated with near-fatal clinical presentation within 1 hour. This reaction was independent of mice strain as both BALB/c and C57BL/6 developed reactions. The reactions were not due to LPS because LPS receptor mutant C3H/Hej mice also exhibited reactions. The reactions were not allergic because low/non-IgE responder SJL mice and IgE receptor knockout (KO) mice also exhibited such reactions. Furthermore, these mice had no detectable antibodies (IgE or IgG1) to walnut. We found that the acute near-fatal reactions were associated with severe hypotension and bradycardia. Surprisingly, the complement C3 KO mice and the C3a receptor KO mice were resistant to walnut induced hypotensive shock responses. These data demonstrate for the first time that walnut extract induces near-fatal acute anaphylactoid shock via the innate complement system in naïve mice.
Invariant NKT cells are crucial for airway inflammation induced by environmental antigens (163.22)
Authors: Wingender Gerhard , Rogers Paul , Batzer Glenda , Lee Myung , Bai Dong , Khurana Archana , Kronenberg Mitchell , Horner Anthony 
Published: January 2023

Abstract
Invariant NKT (iNKT) cells are a unique subset of T lymphocytes that rapidly carry out effector functions. Here we report that a majority of sterile house dust extracts (HDEs) tested contained antigens capable of activating mouse and human iNKT cells. HDEs had adjuvant-like properties in an ovalbumin-induced asthma model, that were dependent on Vα14i NKT cells, as vaccinated animals deficient for iNKT cells displayed significantly attenuated immune responses and airway inflammation. Furthermore, the administration of HDEs together with ovalbumin mutually augmented the synthesis of cytokines by Vα14i NKT cells and by conventional CD4+ T cells in the lung, demonstrating a profound immune response synergy for both Th2 cytokines and IL-17A. These data demonstrate that iNKT cell antigens are far more widely dispersed in the environment than previously anticipated. Furthermore, as the antigenic activity in different houses varied greatly, they further suggest that iNKT cell responses to ambient antigens, particular to certain environments, might promote sensitization to conventional respiratory allergens.
PARP-1 deficiency blocks IL-5 expression through calpain-dependent degradation of STAT-6 in a murine asthma model (163.6)
Authors: Naura Amarjit , Datta Rahul , Zerfaoui Mourad , Errami Youssef , Oumouna Mustapha , Kim Hogyoung , Jihang Ju , Ronchi Virginia , Haas Arthur , Boulares Hamid 
Published: January 2023

Abstract
We recently showed that PARP-1 plays a role in allergen (Ovalbumin)-induced airway eosinophilia, potentially through a specific effect on IL-5 production. Here we have explored the mechanism by which PARP-1 regulates IL-5 production using a murine model of allergic airway inflammation and splenocytes derived from wild type or PARP-1-/- mice. We show that PARP-1 knockout-associated reduction in IL-5 upon allergen exposure occurs at the mRNA level. Such an effect appears to take place after IL-4 receptor activation as PARP-1 inhibition exerted no effect on JAK1/JAK3 activation. STAT-6 protein was severely downregulated in spleens of PARP-1-/- mice without any effect on mRNA levels, suggesting an effect on protein integrity rather than gene transcription. Interestingly, the degradation of STAT-6 in PARP-1-/- mice required allergen stimulation. The dowregulation of STAT-6 coincided with mRNA and protein reduction of GATA-3 and occupancy of its binding site on the IL-5 gene-promoter. IL-4 was sufficient to induce STAT-6 downregulation in both PARP-1-/- mice and isolated splenocytes. Such degradation may be mediated by calpain, but not by proteasomes. Our results demonstrate a novel function of PARP-1 in regulating IL-5 expression during allergen-induced inflammation and explain the underlying mechanism by which PARP-1 inhibition results in IL-5 reduction.
Regulation of Allergic Airways Disease by CD4+ T cells engineered to overexpress Interleukin-17 (163.7)
Authors: Nakada Emily , Kinyanjui Margaret , Fixman Elizabeth 
Published: January 2023

Abstract
Background: Clinical data have associated Th17 cells, IL-17 and neutrophilia with severe asthma. The objective of these experiments is to assess how T cell specific overexpression of IL-17 modifies OVA-induced airway inflammatory responses using an adoptive transfer murine model. Methods: Recombinant retroviruses encoding either EGFP alone (pAP2) or both EGFP and IL-17 were used to transduce CD4+ T cells from OVA-sensitized donor BALB/c mice, re-stimulated with OVA ex vivo for targeted retroviral transduction. CD4+ T cells were isolated using magnetic selection and adoptively transferred intraperitoneally into naïve mice on day 0. Recipients were then anaesthetized and challenged intranasally with OVA daily for 5 days. Mice were sacrificed 24h after the final challenge. Results: Recombinant retroviruses efficiently transduced CD4+ T cells after re-stimulation with OVA such that 0.17% of T cells transduced with control virus expressed IL-17 vs 4.65% of T cells transduced with IL-17pAP2. Supernatants from IL-17pAP2 transduced cells produced abundant IL-17, which was undetectable in pAP2 transduced cells. Following adoptive transfer and challenge, IL-17 levels in the bronchoalveolar lavage fluid (BALF) of recipients from the IL-17pAP2 group were greater than those from the pAP2 control group. BALF levels of inflammatory cells were increased in each group. This model will allow us to define how allergic airway inflammation is modified by T cell specific IL-17 overproduction.
Gender specific increase of IL-17A in a murine model of asthma in the absence of T-bet (163.8)
Authors: Koch Sonja , Übel Caroline , Finotto Susetta 
Published: January 2023

Abstract
Recent studies in humans have suggested that females may be more susceptible to allergic asthma than male. In addition, studies in Balb/c mice revealed that females have higher serum IgE levels, Th2 cytokines and an increased number of CD4+ T-cells. Mice lacking the Th1-specific transcriptional factor T-bet (T-bet-/-) show a severe phenotype of asthma with increased AHR, eosinophils and Th2 type cytokines in their airways. We therefore analyzed gender specific immune-responses in T-bet-/- mice in a murine model of allergic asthma. To this aim, we first looked at the Th2 inducing cytokine IL-6 and found it induced in the airways of naïve T-bet-/- mice. IL-6 inhibits T regulatory cells and together with TGFβ1 induces Th17 cells. We then studied the expression of different cytokines involved in the development of the Th17-pathway in a gender dependent manner. We found that total lung cells isolated from asthmatic female T-bet-/- mice release increased levels of IL-6, TGFβ1 and IL-17 compared to the male littermates. Consistently, in these mice, other cytokines of the Th17-pathway like IL-23 and IL-21 were also found induced in the lung of female T-bet-/- mice as compared to the levels measured in the lung of males. These results might explain why females are more susceptible than males to some aspects of asthma and therefore gender specific studies in asthma might help to better design therapies for this disease.
Identification and analysis of lipid mediators in a mouse model of allergic contact dermatitis (163.9)
Authors: Chen Huan-Yuan , Yang Jun , Inceoglu Ahmet Bora , Wang Li-Chieh , Yu Lan , Hammock Bruce , Liu Fu-Tong 
Published: January 2023

Abstract
Allergic contact dermatitis (CD) is a type of inflammatory skin disease resulting from delayed-typed hypersensitivity to haptenic antigens. The antigens are presented to T cells by dendritic cells in the skin and result in activation and recruitment of other immune cells to the skin. The inflammatory response is frequently accompanied by production of metabolic mediators. Here we sought to identify mediators involved in allergic CD by using a mouse model. C57BL/6 mice were sensitized with dinitrofluorobenzene or oxazolone and challenged with the same antigen on the ear. The treated ears were swollen and exhibited accumulation of leukocytes. The affected ears were subjected to targeted quantitative metabolomic analysis by mass spectrometry to identify lipid metabolites that displayed significant changes. A cyclooxygenase product, thromboxane A2, was remarkably induced by more than 10 fold compared to vehicle control. A number of other bioactive lipid metabolites were induced by more than two fold. We found that mice treated with aspirin or sEHi showed reduced ear thickness compared to vehicle treatment. Our data suggest that the cyclooxygenase and soluble epoxide hydrolase pathways are involved in the development of allergic CD by modulating the inflammatory skin response. Inhibitors of these two pathways and antagonists of prostanoid receptors for the elevated metabolites are expected to be effective therapeutically to treat allergic CD.
Astrocyte-specific blockade of the IL-17 pathway reduces disease severity of experimental autoimmune encephalomyelitis (164.11)
Authors: Yan Yaping , Ding Xiaoli , Li Ke , Rostami Abdomohamad , Zhang Guang-xian 
Published: January 2023

Abstract
IL-17 is crucial for the progression of experimental autoimmune encephalomyelitis. Through neutoectoderm-specific knockout studies, it has been shown that astrocyte-restricted ablation of IL-17 induced, Act1-mediated signaling ameliorates autoimmune encephalomyelitis. However, it is difficult to translate these results into therapy because of: 1) complex functions of Act1; 2) potentially severe side effects from constitutively repressed Act1 expression; and 3) impracticality of knockout model for human therapy. To overcome these weaknesses, we have established a GFAP promoter driving miR-30 based shRNA cassette targeting Act1 to knockdown expression of Act1 and block the IL-17-IL-17R pathway in astrocytes, and tested its therapeutic effect on ongoing EAE. Intracerebroventricular (i.c.) injection of 2×106 IU/mouse of GFAP-miR-shAct1-EGFP lentivirus significantly inhibited disease progression and severity of ongoing chronic EAE in MOG-immunized C57BL/6 mice. Further analysis showed that astrocyte-specific blockade of the IL-17 pathway greatly reduced the number of mononuclear cells in central nervous system, partially due to reduced expression of chemokines, such as CXCL1, CXCL2, CCL20 and MMP3, which are necessary for the recruitment of peripheral leukocyte infiltration during EAE pathogenesis. These results suggest that astrocyte-specific blockade of the IL-17 pathway can be a promising way to treat neuroinflammatory diseases.
RTL551-mediated treatment of EAE involves reduction in CD226 and T-bet expressing pathogenic CD4+ T-cells (164.12)
Authors: Sinha Sushmita , Miller Lisa , Vandenbark Arthur , Halina Offner 
Published: January 2023

Abstract
Recombinant T cell receptor ligands (RTLs) reverse clinical and histological signs of EAE in an antigen specific manner, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTLs on expression of two pathogenic T-cell maturation markers, CD226 and T-bet, by CD4+ Th1/Th17+ cells in a MOG-35-55 peptide-induced model of EAE. A single injection of RTL551 (two-domain I-Ab covalently linked to MOG-35-55 peptide), but not the control RTL550 (“empty” two-domain I-Ab without a bound peptide), reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced expression of CD226 and T-bet on blood-borne MOG-35-55-specific CD4+ T-cells and inhibited expansion of CD44 expressing CD4 cells in blood and spleen. Concomitantly, RTL551 selectively reduced absolute numbers of T-bet+ CD4+ T-cells and IL-17 and IFN-γ secretion in the CNS. These novel data demonstrate that a major effect of RTL therapy is to prevent maturation of memory T-cells that mediate clinical signs and CNS inflammation in EAE.
Highly specific and reliable biomarker of human MM cells in NOD/SCID animal models through the cancer/testis antigen AKAP-4: new opportunities for pharmacological studies (165.17)
Authors: Chiriva Maurizio , Mirandola Leonardo , Yu Yuefei , Jenkins Marjorie , Cobos Everardo , John Constance 
Published: January 2023

Abstract
Despite recent findings for the treatment of multiple myeloma (MM) it still remains a deadly disease. In the effort to develop new and more effective therapies for human tumors, murine animal models have been proven critical for a variety of neoplasias. Unfortunately, although recent studies have described different animal models of human MM, none is available for tracking the tumor progression with a specific biomarker employing human MM cells. This lack hampers the development of new approaches for treating MM. Here we describe a human MM model in NOD/SCID mice that allows for highly sensitive and specific monitoring of disease progression through the endogenously-expressed tumor specific cancer/testis antigen AKAP-4. The human MM cells U266 were subcutaneously injected in NOD/SCID animals. AKAP-4 expression resulted to be a reliable and sensitive antigen to monitor tumor growth and spread by different and independent techniques, namely flow-cytometry, E.L.I.S.A., Western blot and RT-PCR. The relevance of our findings stems from the suitability of this innovative model for a thorough pre-clinical evaluation of experimental pharmacological strategies for the treatment of human MM.
Pro-apoptotic effect of increasing miR15a/16-1 expression by different strategies in B-CLL cells (165.28)
Authors: Kasar Siddha , Underbayev Chingiz , Yuan Yao , Hanlon Matthew , Mehta Smruti , Neuberger Eric , Raveche Elizabeth 
Published: January 2023

Abstract
Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoid malignancy characterized by accumulation of mature CD5+ B-cells in peripheral lymphoid organs, bone marrow and peripheral blood and is incurable with conventional therapy. We have previously shown that similar to human B-CLL cells, NZB mice (de novo mouse model of CLL) have 50% less level of miR15a/16-1 (pro-apoptotic). We hypothesized that exogenously increasing their expression would lead to increased apoptosis in tumor cells. Using a lentiviral delivery system, we were able to stably increase the level of these two microRNAs in LNC (NZB derived B-CLL cell line). The apoptosis observed in miR-GFP transduced LNC was twice as much as in LNC transduced with GFP lentivirus (control). In addition to the miR defect, B-CLL cells have a very high level of B-cell specific activator protein (BSAP) and this prevents their terminal differentiation. Recent reports have suggested that BSAP and miR15a/16-1 form an autoregulatory loop. We found that the level of the two oncoproteins BSAP and c-Myb were reduced in the miR-GFP transduced cells as compared to the control. Alternatively, we found that the miR defect can also be corrected by knocking down BSAP (using RNAi) leading to a cell cycle arrest. The second strategy is clinically relevant, since developing a BSAP inhibitor is more feasible than systemic microRNA delivery. Based on our findings we propose that targeting BSAP could be used as a novel therapeutic strategy for B-CLL.