bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depletion of FoxP3+T-cells enhances anti-MHC class I induced autoimmunity in FoxP3DTR transgenic murine model: role in pathogenesis of chronic rejection (115.12)
Authors: Tiriveedhi Venkataswarup , Takenaka Masashi , Ramachandran Sabarinathan , Patterson Alexander , Mohanakumar T. 
Published: January 2023

Abstract
Recent evidence strongly suggest that alloimmunity induced autoimmune process plays an important role in the development of chronic rejection following human lung transplantation. We have previously shown that intrabronchial administration of MHC Class I antibodies (Abs) to mice causes obliterative airway disease (OAD, which is considered as a model for chronic rejection following human lung transplantation. Our goal is to study the impact of FoxP3+ regulatory T-cells (Tregs) in this established murine model of OAD. FoxP3DTR transgenic Bl/6 mice (kindly provided by Dr. Rudensky), following diphtheria toxin (DT) administration the Treg frequency at 48hrs decreased by 98%. Intrabronchial administration of H2Kb Abs into DT treated mice demonstrated a 3 fold increase in airway lesions and fibrous deposition over non-Treg depleted animals. Antibody concentrations to self antigens increased from 154 ± 32 to 265 ± 48 µg/mL for Collagen-V and 243 ± 43 to 394 ± 48 µg/mL for K- α1Tubulin. ELISpot analysis for Th-precursor frequency showed enhanced levels of IFN-γ (2.3 fold), IL-17 (3.3 fold) and decreased levels of IL-10 (4.1 fold) in Treg depleted cohort. RT-PCR analysis on lung tissue demonstrated upregulation of chemokines and pro-fibrotic growth factors in Treg depleted cohort. We conclude that depletion of T reg increases the severity of OAD as well as development of autoimmune responses to self-antigens leading to pathogenesis of chronic rejection.
Retina-specific T regulatory cells accumulate in the eye during autoimmune uveitis and act to control inflammation (115.22)
Authors: Caspi Rachel , Horai Reiko , Chen Jun , Hansen Anna , McManigle William , Villasmil Rafael , Silver Phyllis 
Published: January 2023

Abstract
Experimental autoimmune uveitis (EAU) induced in mice by immunization with the retinal antigen IRBP is a model of human autoimmune uveitis. We examined whether T regulatory (Treg) cells found in uveitic eyes are (i) IRBP specific, (ii) functionally suppressive, and (iii) may play a role in natural resolution of disease. EAU was induced in B10.RIII FoxP3-GFP reporter mice with IRBP161-180. IRBP-specific T cells were detected by staining with IRBP-MHC class II dimers. In uveitic eyes, progressive increase of FoxP3+ Treg to T effector (Teff) ratio correlated with resolution of disease. At peak disease up to 20% of Treg (CD4+FoxP3+) and up to 60% of Teff (CD4+FoxP3-) in inflamed eyes were IRBP specific by dimer staining, while in lymphoid organs dimer-positive T cells were undetectable. Treg sorted from eyes of mice with EAU efficiently suppressed antigen-driven proliferation not only of naïve IRBP specific T cells (from IRBP TCR transgenic mice), but also of Teff from the same eyes. Importantly, depletion of Treg at the peak of EAU (using FoxP3-diphtheria toxin receptor transgenic mice) delayed resolution of disease. Thus, the T cell infiltrate in uveitic eyes of mice that have a polyclonal T cell repertoire is highly enriched in IRBP-specific Treg and Teff cells. Unlike what has been reported for Treg in other inflammatory sites, Treg in uveitic eyes are unimpaired functionally. Finally, FoxP3+ Treg appear to play a role in the natural resolution of autoimmune ocular disease.
Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN by TLR7/9 (116.20)
Authors: Liu Yi , Simmons Daimon , Li Xiaoxia , Abbott Derek , Boom W. , Harding Clifford 
Published: January 2023

Abstract
TLR9 signaling induces type I IFN (IFN-I), which enhances MHC-I Ag cross processing, but TLR2 signaling does not. Moreover, we previously reported that TLR2 signaling by Mycobacterium tuberculosis (Mtb) or other TLR2 agonists inhibited TLR9 induction of IFN-I and IFN-I-dependent MHC-I Ag cross processing (Simmons, 2010, J. Immunol.). In the current studies, a TLR2 agonist inhibited IFN-I mRNA induction when added together with TLR9 agonist for 2 to 24 h. TLR2 agonist inhibited TLR9-induced first wave IFN-I, since the inhibition was manifested in IFN-I receptor knock out DCs, which lack the second wave positive feedback mechanism, whereas second wave IFN-I mRNA induction by exogenous IFN-I was not inhibited. TLR2 also inhibited IFN-I induced by TLR7, another MyD88-dependent IFN-inducing receptor, but did not inhibit IFN-I induction by TLR3 or TLR4 (both TRIF-dependent, MyD88-independent). The inhibitory effect of TLR2 was not dependent on new protein synthesis or intercellular signaling. Current studies are further addressing the intracellular mechanism whereby TLR2 inhibits induction of IFN-I. This novel mechanism, whereby TLR2 inhbits IFN-I induction by TLR7/9, may shape immune responses to microbes that express ligands for both TLR2 and TLR7/TLR9, or responses to bacteria/virus coinfection.
Critical link between intracellular responses and innate autoimmunity in ischemia-reperfusion injury (116.26)
Authors: Lee Haekyung , Ko Eun Hee , Lai Chih , Wei Na , Balroop Javi , Richardson Arlan , Zhang Ming 
Published: January 2023

Abstract
Reperfusion of the ischemic tissue may lead to acute ischemia/reperfusion (I/R) injury. Intracellular responses to ischemia involve reactive oxygen species (ROS), while extrinsic acute inflammation manifests as natural IgM-mediated innate autoimmunity. Whether the ROS-mediated mechanism plays a role in the natural IgM-mediated mechanism is unknown. We studied this important question by using transgenic (tg) mice overexpressing superoxide dismutase (SOD1) in a murine intestinal ischemia model. Our results showed that SOD1 tg mice have a significant reduction in intestinal tissue damage compared with WT littermates. IgM-mediated complement activation is also blocked in SOD1 tg mice. We explored whether cell membrane damage is the critical step between the generation of intracellular ROS and the innate autoimmune response. A cell membrane stabilizer was applied to WT mice in I/R model and significantly protected them from IgM/complement mediated intestinal damage. To investigate its therapeutic application in human ischemic diseases, we tested this stabilizer in a hypoxia model of human coronary artery endothelial cells (hCAECs). Our results showed that under hypoxia, human IgM and C3 deposited on hCAEC, suggesting activation of complements similar to that in animal I/R model. We have identified a critical link between the intracellular response to I/R injury and the first step in the innate autoimmune response. This finding could lead to new treatment approach of I/R injury.
Optimal signaling and effector functions induced by Fcγ-receptor engagement on macrophages require both selenoprotein K and high-avidity immune complexes (116.27)
Authors: Huang Zhi , Hoffmann FuKun , Fay Jeffrey , Hashimoto Ann , Hoffmann Peter 
Published: January 2023

Abstract
Selenoprotein K (Sel K) is an endoplasmic reticulum (ER) transmembrane protein that we have recently shown to play a role in calcium-dependent immune cell activation. Sel K-knockout mice exhibit deficient calcium flux in immune cells and impaired immune responses. In this study, we demonstrated that Sel K deletion resulted in decreased FcγR-mediated phagocytosis in mouse bone marrow derived macrophages (BMDM) compared to WT controls. To engage FcγR on BMDM, immune complexes (IC) were added comprised of either IgG-opsonized BSA (low avidity) or IgG-opsonized, BSA-coated beads (high avidity). Both types of IC induced Ca2+-dependent phosphorylation of ERK, but this was significantly decreased in Sel K-/- BMDM compared to controls. Nitric oxide (NO) was only induced with high avidity IC and was significantly decreased in Sel K-/- BMDM. PGE2, IL-6, and TNFα were induced by high avidity IC, but not low avidity IC, and were significantly reduced in Sel K-/- BMDM. Phagocytosis of high avidity IC produced lower oxidative burst in Sel K-/- BMDM. Consistent with this reduced oxidative burst, there was reduced destruction of IgG-opsonized West Nile virus in the phagolyzosome of Sel K-/- BMDM compared to controls. Overall, these results suggest that Sel K plays a role in FcγR-mediated signaling and effector functions of macrophages, and high avidity IC are required to induce maximal effects.
Adenosine receptor activation augments IL-10 production by murine microglial cells (116.31)
Authors: Koscso Balazs , Selmeczy Zsolt , Himer Leonora , Csoka Balazs , Hasko Gyorgy 
Published: January 2023

Abstract
Microglia, the intrinsic macrophages of the central nervous system produce the anti-inflammatory cytokine IL-10 following activation with the bacterial cell wall product peptidoglycan (PGN), which is recognized by Toll-like receptor 2 (TLR2). Adenosine is an endogenous purine nucleoside that binds to specific G protein-coupled receptors (A1, A2A, A2B, and A3), and is a well known modulator of the immune system. In this study we investigated the effect of adenosine on IL-10 production by microglia. Cells were treated with adenosine, or selective adenosine receptor agonists and antagonists, in conjunction with 20 μg/ml PGN for 6 or 24 hours. Adenosine treatment augmented IL-10 production by microglia activated with PGN. The non-selective adenosine receptor agonist NECA was the most potent IL-10 inducer, and its effect was prevented by pretreatment with the A2B antagonist MRS-1754. Adenosine receptor activation augmented IL-10 mRNA levels, and this effect was prevented by blocking transcription with actinomycin D. The stimulatory effect of adenosine on IL-10 production was mediated by p38 because it was reversed with a p38 pathway inhibitor. IL-10 promoter analysis and chromatin immunoprecipitation (CHIP) experiments suggested that CREB activation is necessary for the effect of adenosine. These results demonstrate that A2B adenosine receptor activation augments IL-10 production by PGN-activated microglial cells through a p38- and CREB-mediated pre-transcriptional mechanism.
Coordinate stimulation of macrophages by microparticles and TLR ligands promotes foam cell formation (116.9)
Authors: Keyel Peter , Tkacheva Olga , Watkins Simon , Larregina Adriana , Salter Russell 
Published: January 2023

Abstract
Macrophage dysregulation through the uptake of and signaling by oxidized lipoproteins can lead to atherosclerosis. Recent evidence shows that Toll-like Receptor signaling plays an emerging role in the onset of atherosclerosis by increasing foam cell formation. To investigate the link between TLR signaling and foam cell formation, we established an in vitro assay utilizing liposomes of defined lipid compositions. We found that TLRs signaling through Trif promoted foam cell formation by inducing Type I IFN production, whereas TLRs that do not induce IFN, like TLR2, did not enhance foam cell formation. However, in combination with IFNα, TLR2 did promote robust foam cell formation. We then investigated the ability of microparticles to also contribute to foam cell formation. We found that both exosomes and ectosomes promoted foam cell formation and macrophage activation, and was enhanced by TLR stimulation or IFNα. To dissect the temporal kinetics, we sequentially added microparticles and LPS. We found that activation of the macrophages with LPS prior to microparticle treatment, but not vice versa, led to enhanced foam cell formation, suggesting that previously activated macrophages are more prone to foam cell formation. Finally, microparticles stimulated foam cell formation in a tissue model. Taken together, these data suggest that foam cell formation can be triggered by microparticles in the context of TLR stimulation.
Basal and induced IL-1α versus IL-1β mRNA expression (117.10)
Authors: Moon Morgan , Joesting Jennifer , Freund Gregory 
Published: January 2023

Abstract
Interleukin (IL)-1β is a critical and comprehensively studied proinflammatory cytokine that signals through IL-1r1. However, IL-1β may not be the only IL-1 with important actions. While IL-1α shares the signaling pathway with IL-1β, much less is known about the importance of IL-1α in health and disease. Utilizing several whole tissues, isolated cells and cell lines, we examined the ratio of IL-1α and IL-1β mRNA expression. The ratio of IL-1α to IL-1β in brain and liver were similar, but differed from the ratio observed in adipose and spleen. To investigate a possible cellular source of these differences, we isolated microglia from whole brain. These cells, as well as the BV2 microglial cell line, demonstrated an IL-1 ratio similar to brain expression. BV2 cells were then challenged with endotoxin to determine if an inflammatory stimulus altered the IL-1 ratio. Indeed, while both IL-1α and IL-1β were upregulated after LPS treatment, the relative expression changes were different and altered the IL-1 ratio from its basal state. We have shown that not only does the IL-1 ratio differ between tissues, but also with immune stimulation. These data suggest that within the numerous functions of the IL-1 super family, actions of IL-1α and IL-1β may vary depending on tissue, cell and host status.
Detection of IL-12 family members p35, Ebi3, and p19 in response to TLR agonists by flow cytometry and ELISA (117.12)
Authors: Schifano Matthew , Ruiz Natalie , Li Shourong , Atteberry Brandi , Huang Qiulong , Schrantz Nicolas , Just Peggy 
Published: January 2023

Abstract
Myeloid cell-derived, cytokine-mediated signals are critical to the differentiation and maintenance of T helper cell responses. Monocytes, macrophages and dendritic cells are especially instrumental in initiating these responses through secretion of members of the interleukin (IL)-12 family of heterodimeric cytokines. IL-12 and IL-27 are necessary for the differentiation of T helper(h) 1 cells and IL-23 is required for the maturation and maintenance of Th17 cells. The secretion of these cytokines by monocytes, macrophages and dendritic cells is induced by a variety of pathogens, which can affect secretion by the activation of different signaling pathways. Here we use novel intracellular flow cytometry reagents and enzyme-linked immunosorbent assay (ELISA) to show the effects of different TLR agonists on the secretion of IL-12 family members, including Ebi3, p40, p19 and p35.
Role of resistin like molecule α in pulmonary arterial remodeling induced by the response to antigen and urban particulate matter. (117.22)
Authors: Pflanz Stefan , Hoffman Carol , Sisco Maureen , Bleck Bertram , Gordon Terry , Reibman Joan , Grunig Gabriele 
Published: January 2023

Abstract
Our studies focused on the role of resistin like molecule α (RELMα) in severe pulmonary arterial remodeling induced by a T helper 2 (Th2) response to antigen. We studied wild type and RELMα deficient mice following immunization with Ovalbumin (OVA) complexed to Alum and exposure to soluble OVA alone or in combination with respirable urban particulate matter. The urban particulate matter (PM2.5) was collected from the air in New York City. Our studies demonstrated a significant exacerbation of pulmonary arterial remodeling in antigen primed wild type mice exposed to a combination of antigen and urban particulate matter. RELMα deficient mice, in contrast, failed to show the exacerbation and developed pulmonary arterial thickening to exposure with antigen and respirable urban particulate matter to a significantly smaller degree relative to wild type. The severity of inflammation and the type of the immune response in the RELMα deficient mice challenged with antigen or the combination of antigen and urban particulate matter was not significantly different from the responses in wild type mice. RELMα is known to have a critical role in hypoxia induced pulmonary arterial remodeling and to be induced by hypoxia. Airborne metals mimic hypoxia induced cell signaling. Therefore, our data suggest the idea that both antigen and urban pollution induce RELMα signaling via two independent, but additive pathways.
IL-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL from synovial fibroblasts (117.25)
Authors: Lee Sang-Heon , Kim Kyoung-Woon , Kim Hae-Rim , Seo Young-Il 
Published: January 2023

Abstract
This study aims to determine the regulatory role of interleukin(IL)-22 on the expression of receptor activator of NF-kB ligand(RANKL) and the induction of osteoclastogenesis in rheumatoid arthritis(RA). The concentrations of IL-22 and RANKL in sera and synovial fluids(SF)of RA patients were measured by ELISA. After RA synovial fibroblasts were treated with rhIL-22, the expression of RANKL mRNA and protein was determined using real-time PCR,western blot,and immunostaining.Human monocytes were cocultured with IL-22-prestimulated RA synovial fibroblasts and monocyte-colony stimulating factor(M-CSF), and then osteoclastogenesis was determined by counting of TRAP-positive multinucleated cells. Serum and SF IL-22 concentration in RA patients was higher than in osteoarthritis patients and healthy subjects. When RA synovial fibroblasts were treated with rhIL-22, the expression of RANKL mRNA and protein was upregulated in a dose-dependent manner. The IL-22-induced RANKL expression was significantly down-regulated by inhibition of p38 MAPK/NF-kB and JAK-2/STAT3. When human monocytes were cultured with IL-22-prestimulated RA synovial fibroblasts in the absence of RANKL, the monocytes were differentiated into osteoclasts, which was blocked by the inhibition of p38 MAPK/NF-kB and JAK-2/STAT3.Our results suggest that IL-22 up-reugulates RANKL expression in RA synovial fibroblasts and it also promotes osteoclastogenesis, which are mediated by p38 MAPK/NF-kB and JAK-2/STAT3 pathways.
Contribution of functional IL-18 promoter polymorphisms to the risk of idiopathic recurrent spontaneous miscarriage (117.29)
Authors: Al-Khateeb Ghada , Sater Mai , Almawi Wassim 
Published: January 2023

Abstract
Interleukin (IL)-18 is a proinflammatory cytokine, which modulates Th1 differentiation and CTL effector activity, both of which were implicated in the pathogenesis of recurrent spontaneous miscarriage (RSM). We evaluate the association of single nucleotide polymorphisms (SNPs) in the IL18 gene promoter at -656G/T (rs1946519),-137G/C (rs187238), -119T/G (rs360718), and -105T/C (rs360717), were detected by TaqMan assays in analysis in 277 RSM cases and 283 control women matched for age and ethnic background; serum IL-18 level was measured by ELISA. Association of IL-18 alleles, genotypes, and haplotypes with RSM were evaluated by Fisher's exact test and regression analysis. The -656T (P&lt;0.001; OR, 1.87; 95% CI, 1.44-2.42) and -105C (P&lt;0.001; OR, 2.00, 95% CI, 1.54-2.59) alleles, significantly increased RSM risk. Significant differences in the distribution of -656G/T and -105T/C genotypes were seen between RSM cases and controls; no association was found between -137G/C or -119T/G and RSM. Haploview analysis revealed linkage disequilibrium between VEGF SNPs analyzed SNPs. Four-locus (rs1946519/rs187238/rs360718/rs360717) haplotype analysis identified two RSM-protective (1111 and 1222) and two RSM-susceptible (1112 and 2112) haplotypes. Multivariate analysis confirmed the positive association of 2112 haplotype with RSM, after controlling for a number of covariates. These results demonstrate that the VEGF polymorphisms are significantly associated with idiopathic RSM.
The Axl/Gas6 phagocytosis receptor system is constitutively upregulated by Langerhans cells in response to epidermal TGF-β1. (147.15)
Authors: Bauer Thomas , Jurkin Jennifer , Yasmin Nighat , Zagorska Anna , Lemke Greg , Strobl Herbert 
Published: January 2023

Abstract
Tyro-3, Axl and Mer (TAM) receptor tyrosine kinases represent an anti-inflammatory phagocytosis system, which is upregulated on myeloid cells by interferon-α during inflammation. These receptors use their ligands protein S and Gas6 for recognizing phosphatidylserine on apoptotic cells. Activation leads to a block in pro-inflammatory cytokine production, therefore implicating this system in silent phagocytosis and resolution of inflammation. We here identified Axl to be induced by TGF-β1 during Langerhans cell commitment of human CD34+ myeloid progenitor cells and monocytes. Axl surface expression was specific for LCs, since it could not be detected in other myeloid DC subsets and macrophages. We further demonstrate that Axl and Gas6 are upregulated in human skin in vivo; strong induction was seen in the suprabasal keratinocyte layers, thereby co-localized with TGF-β1. Vitamin K activates TAM ligands; accordingly VK addition promoted in vitro LC differentiation and enhanced E-cadherin expression; conversely antibody inhibition of Axl showed an inverse effect. TAM KO mice exhibited reduced LC numbers, and this effect preceded the development of lupus like disease and associated skin inflammation previously identified in these mice. Therefore, TGF-β1 controls the steady-state expression of Axl in DCs. Constitutive Axl expression by epidermal LCs may play a key role during silent phagocytosis and resolution of inflammation, previously known to be largely dependent on TGF-β.
Dexamethasone selectively retains tolerogenic macrophages in the spleen (147.19)
Authors: Chen Aoshuang , Munirathinam Gnanasekar , Zhong Shibo , Cha Isaac , Reardon Catherine , Getz Godfrey , Kang Youmin , Wang Bin , Zheng Guoxing 
Published: January 2023

Abstract
We previously showed that the immunosuppressant dexamethasone (DEX), when used as a “tolerogenic adjuvant” during antigenic immunization, preferentially expands Ag-specific CD4+CD25+Foxp3+ regulatory T cells (Treg) and forcefully steers the immunization toward Ag-specific tolerance. However, the mechanisms underlying the tolerogenic efficacy of DEX remain undetermined. In this study, we show that while dose-dependently depleting dendritic cells in the spleen and lymph nodes, DEX selectively retains and modifies in the spleen a macrophage subset expressing low levels of CD11c (designated “DEX-MΦs”). DEX-MΦs constitutively express CD86 and, yet, down-regulate MHC II. Upon recall-Ag stimulation, DEX-MΦs upregulate IL-10, a classic marker for tolerogenic APCs. When presenting recall Ag in vivo, DEX-MΦs do not elicit responses of effector T cells, but rather stimulate the expansion of Ag-specific Treg. Thus, we suggest that DEX may exert its adjuvant efficacy partly by selectively retaining tolerogenic DEX-MΦs and using them as the alternate APCs.