bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interaction of PKC, S100A4, and the cytoplasmic domain of FcγRIIIa (CD16A) α-chain regulates receptor mediated functions (116.1)
Authors: Li Xiaoli , Baskin Julie , Mangan Erin , Yang Xiaoli , Su Kaihong , Gibson Andrew , Ji Chuanyi , Edberg Jeffrey , Kimberly Robert 
Published: January 2023

Abstract
FcγRIIIa(CD16A) pairs with FcR-common γ-chain for surface expression and function. Since many functionally distinct immune receptors utilize γ-chains as signaling subunit, we hypothesized that elements for specificity in receptor signaling may be determined by the distinct FcγR cytoplasmic domains (CY). In silico analysis identified a PKC phosphorylation consensus motif within CD16A-CY; and in vitro kinase assays demonstrated that it is specifically phosphorylated by PKC. Non-phosphorylated CD16A is more effective at activation of the Gab2/PI3K pathway, leading to enhanced degranulation, while phosphorylated CD16A mediates a more robust calcium flux, tyrosine phosphorylation of Syk and pro-inflammatory cytokine production. S100A4, a specific protein binding partner for CD16A-CY, inhibits phosphorylation of CD16A-CY by PKC in vitro. Reduction of S100A4 levels in vivo enhanced receptor phosphorylation upon cross-linking. Taken together, we show that among IgG and IgA receptors, PKC-mediated phosphorylation of CD16A is specific and modulates distinct signaling pathways engaged by the receptor. Calcium activated binding of S100A4 to CD16A, promoted by the initial calcium flux and attenuating the phosphorylation of CY, may serve as a negative feedback on cytokine production pathways during sustained receptor engagement and favor a shift to degranulation, consistent with the importance of degranulation following conjugate formation between CD16A+ effector cells and target cells.
Adenosine promotes alternative macrophage activation by triggering an A2B receptor-initiated p38-C/EBPβ signaling cascade (116.2)
Authors: Csoka Balazs , Koscso Balazs , Nemeth Zoltan , Selmeczy Zsolt , Deitch Edwin , Hasko Gyorgy 
Published: January 2023

Abstract
There are two types of macrophage (MΦ) activation. Classical MΦ activation (M1) is driven by TLR ligands and IFNγ, while alternative MΦ activation (M2) is triggered by Th2 cytokines. Adenosine exerts its actions by activating the G protein-coupled receptors, A1, A2A, A2B and A3. The role of adenosine in regulating M1 MΦ activation is well established; however, our understanding about its impact on M2 MΦ activation is not clear. Therefore, we investigated the effect of the adenosine on IL-4-driven M2 MΦ activation. We found, that adenosine enhanced the IL-4-induced expression of M2 MΦ activation markers, Arginase-1 and TIMP-1. We demonstrated that the A2B receptor is required for this stimulatory effect. The stimulatory effect of adenosine on M2 MΦ activation was unlikely to be mediated by STAT-6, because we found that IL-4-induced STAT6 phosphorylation was decreased by adenosine. Conversely, the stimulatory effect of adenosine on IL-4-induced arginase activity, and TIMP-1 production was blocked by p38 inhibition, indicating a role for p38. In addition, because adenosine increased IL-4-induced C/EBP luciferase activity, and deficiency of C/EBPβ reversed the stimulatory effect of adenosine on arginase activity, we conclude that C/EBPβ has an essential role in the mediation of adenosine signaling. In summary, our results show that adenosine up-regulates M2 MΦ activation via an A2B receptor-p38-C/EBPβ axis.
Myeloperoxidase acts as a double-edged sword in rotenone-exposed brain-resident immune cells (116.32)
Authors: Chang Chi Young , Song Mi Jeon , Yoon Hee Jung , Jeon Sae-Bom , Suk Kyungho , Kim In-Hoo , Choi Dong-Kug , Park Eun Jung 
Published: January 2023

Abstract
Rotenone exposure has emerged as an environmental risk factor for inflammation-associated neurodegenerative diseases. However, the underlying mechanisms responsible for the harmful effects of rotenone in the brain remain poorly understood. Here, we report that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed brain-resident immune cells. We show that microglia, unlike neurons, do not undergo death, but instead exhibit distinctive activated properties under rotenone-exposed conditions. Once activated by rotenone, microglia show increased production of reactive oxygen species (ROS), particularly hypochlorous acid. Notably, MPO, a hypochlorous acid-producing enzyme that is undetectable under normal conditions, is significantly increased after exposure to rotenone. Interestingly, our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates, rather than inhibits, the rotenone-induced activated state of glia, and promotes glial cell death. Collectively, our data provide evidence that MPO acts a double-edged sword under rotenone-exposed conditions, playing a critical regulatory role in modulating pathological and protective events in the brain.
IL-17 promotes expression of vascular adhesion molecule in vascular smooth muscle cells (117.1)
Authors: Yu Shiguang , Zhang Haitao , Chen Jing , Liu Xiaoming , Awar Lena , Nagarajan Shanmugam 
Published: January 2023

Abstract
Several recent reports showed that IL-17 plays a pro-atherogenic role in atherosclerosis. However the underlying mechanism by which IL-17 promotes the pathogenesis of atherosclerosis remains unclear. The expression of vascular adhesion molecule (VCAM-1) in aortic vascular smooth muscle cells (SMCs) is important for the development of atherosclerosis. We hypothesized that IL-17 may regulate the expression of VCAM-1 in SMCs, as one of potential mechanisms for contributing to atherosclerosis. In this study, we report that IL-17 induces expression of VCAM-1 in SMCs is dependent on NF-κB, but independent of Akt and AP-1 activation. Notably, resveratrol inhibits IL-17-mediated upregulation of VCAM-1 expression. Therefore, blocking IL-17-induced VCAM-1 expression in SMCs may be highly beneficial in treatment of atherosclerosis as VCAM-1 plays a key role for recruitment of inflammatory cells.
An orally active natural product based anti-inflammatory small molecule (RNV-2005) (117.19)
Authors: Nag Bishwajit , Nijjar Sundeep , Sen Ananda , Surve Bhushan , Vutukuru Sriteja , Gulati Shweta , Kr Partha , Srinivasan Narasimhan 
Published: January 2023

Abstract
RNV-2005 is a natural product based molecule originally designed based on its interaction with glucocorticoid receptor (GR). The effective dose of RNV-2005 was found to be in the range of 0.3-10 mg/kg in rodent models. Unlike most analgesic and NSAID compounds, RNV-2005 was non-ulcerogenic up to a tested dose of 200 mg/kg. In an acute toxicity study, RNV-2005 did not show any adverse effect at a highest tested dose of 2000 mg/kg. The LD50 dose of RNV-2005 is therefore not established. A 70-80% reduction in paw edema was observed in animals treated with RNV-2005 at a dose of 10 mg/kg in carrageenan induced paw edema rat model. The analgesic properties of RNV-2005 was measured using tail flick latency and acid induced writhing reflex in Albino mice at doses 0.3-3 mg/kg. In a LPS induced ex-vivo study in SW mice, reduction of cytokines such as TNFα, IL-1β, IL-6 and IL-12 was measured in plasma. Further studies of RNV-2005 in collagen-induced arthritis in DBA/1J mice, adjuvant induced arthritis in Lewis rats, PK studies and in vitro inhibition assays for COX-1 and COX-2 in cell based assays will be presented. Similarly, the molecular mechanisms underlying GR mediated inflammatory responses, with an emphasis on NF-κB and AP-1 and their respective signaling pathways will be discussed. These results with preliminary safety data encourage the clinical potential of RNV-2005 towards development of a novel anti-inflammatory molecule with high therapeutic index.
Individual heterogeneity determines the interaction between human dendritic cells and natural killer cells (147.23)
Authors: Guo Zhenhong , Zhang Hong , Kawamoto Norio , Strominger Jack 
Published: January 2023

Abstract
Previous research has shown that human dendritic cells (DC) can promote activation of natural killer cells (NK), including IFN-γ secretion and enhanced expression of activation markers. However, our recent research suggests that the heterogeneity of individual human donors determines the effect of DC on NK. In our experiments, DC, generated from peripheral blood monocytes and matured by LPS, were co-cultured with autologous NK cells purified from peripheral blood for 24 hours. In the 31 samples, only two donors’ mature DC significantly promoted the secretion of IFN-γ by NK. DC from an additional ten donors promoted the secretion of IFN-γ in the presence of a very low dosage IL-2 or IL-15 which by themselves had no effect. However, all DC could increase expression of CD69 on NK to varying degrees. Further, the DC, not the NK cells, were the key factor for increased IFN-γ secretion because those DC with higher ability to activate autologous NK could also activate allogeneic NK which had otherwise failed to be stimulated with their own autologous DC. Moreover, our current samples did not suggest that the age of the donor was significant for the interaction of NK and DC. Since both NK and DC are very important in infectious disease and cancer immunology, the heterogeneity of NK and DC crosstalk might be related to the susceptibility of some individuals to infection and cancer. However, the mechanisms that determine the effect of DC on NK activation remain to be investigated.
Myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice are only immunosuppressive under serum-free conditions (147.25)
Authors: Hamilton-Valensky Melisa , Lam Vivian , Banáth Judit , Krystal Gerald , Bennewith Kevin 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) are defined by their ability to suppress T cell responses. However, different in vitro culture conditions have been used to assay MDSC function, which may explain why some labs have been unable to demonstrate the suppressive nature of these cells. To address this, we isolated MDSCs from BALB/c mice bearing syngeneic 4T1 metastatic murine mammary tumors and compared the ability of these 4T1-MDSCs to suppress T cell proliferation under serum-containing (10% FCS) and serum-free conditions. Interestingly, we found that these MDSCs only suppressed T cell proliferation under serum-free conditions. Conversely, peritoneal macrophages and tumor-associated macrophages were able to effectively suppress T cell proliferation under both serum-free and serum-containing conditions. These results indicate that serum profoundly alters the immunosuppressive properties of 4T1-MDSCs. We investigated the components of serum responsible for inhibiting the suppressive phenotype of MDSCs and found that 4T1-MDSCs failed to suppress T cell proliferation in serum-free medium supplemented with bovine serum albumin (BSA), yet MDSC suppression in 10% FCS medium was restored when BSA was depleted from the serum. Taken together, these data highlight the importance of testing different in vitro culture conditions on MDSC phenotype to ensure that the presence of serum is not masking the immunosuppressive properties of MDSCs.
Paradoxical role for the lipid phosphatase SHIP1 in control of helminth infection (147.29)
Authors: Hadidi Sima , Hughes Michael , Antignano Frann , McNagny Kelly , Zaph Colby 
Published: January 2023

Abstract
Immunity to helminth infections is mediated by polarized Th2 responses that lead to clearance of infection. One of these responses is the development of AAMs that are associated with intestinal repair and parasite killing. SHIP1 is a lipid phosphatase that negatively regulates immune receptor signaling. Ship1-deficiency in macrophages results in a skewing towards a Th2-type response and the spontaneous development of AAMs. Thus, we hypothesized that macrophage-specific Ship1 knockout mice (Ship1ΔMac) mice would display increased resistance to Trichuris infection. Following infection with Trichuris, cells isolated from Ship1ΔMac mice produced equivalent levels of IL-4, IL-13 and IFN-γ compared to control Ship1fl/fl mice, suggesting that lack of Ship1 in macrophages had little effect on the development of Th2 responses in vivo. Strikingly however-and in contrast to our expectations-Ship1ΔMac mice were more susceptible to infection with Trichuris than control Ship1fl/fl mice. These results demonstrate that macrophage-specific expression of Ship1 is critical for resistance to Trichuris independently of a normally protective Th2 cell response and suggest an alternative role for AAMacs in helminth infection. Thus, these studies identify a novel and paradoxical role for Ship1 in the development of immunity to Trichuris and suggest that manipulation of macrophage function could be critical for inducing or limiting immune responses in the intestine.
Human CD8 T cells drive Th1 responses through differentiation of TNF/iNOS-producing dendritic cells (147.4)
Authors: Chong Shu Zhen , Wong Kok Loon , Lin Gen , Yang Christopher , Wong Siew-Cheng , Angeli Veronique , MacAry Paul , Kemeny David 
Published: January 2023

Abstract
TNF/iNOS-producing (Tip) dendritic cells have been shown to arise during inflammation and are important mediators of immune defense. However, it is still relatively unclear which cell types contribute to their differentiation. Here we show that CD8 T-cells, through the interaction with DCs, can induce the rapid development of human monocytes into Tip-DCs which express high levels of TNF-α and iNOS. These cells exhibited T-cell priming ability, expressed high levels of MHC class II, up-regulated co-stimulatory molecules CD40, CD80, CD86, toll-like receptors TLR2, TLR3, TLR4, chemokine receptors CCR1 and CX3CR1 and expressed the classical mature DC marker, CD83. Differentiation of monocytes into Tip-DCs was partially dependent on IFN-γ as blocking the IFN-γ receptor on monocytes resulted in a significant decrease in CD40, CD83 expression and TNF-α production. Importantly, these Tip-DCs were capable of further driving Th1 responses by priming naive CD4 T-cells for proliferation and IFN-γ production and this was partially dependent on Tip-DC’s production of TNF-α and NO. Our study hence identifies a role for CD8 T-cells in orchestrating Th1-mediating signals through the differentiation of monocytes into Th1-inducing Tip-DCs.
Human multipotent stromal cells inhibit the activation of antigen specific murine CD4+ and CD8+ T cells (147.7)
Authors: Nazarov Cristina , LoSurdo Jessica , Bauer Steven , Wei Cheng-Hong 
Published: January 2023

Abstract
Multipotent stromal cells (MSCs) are known to have immunosuppressive activity. They do not induce allospecific T cell responses, making them promising tools for reducing the severity of graft vs host disease. Although the immunosuppressive effect has been extensively studied, the molecular mechanisms remain elusive. In our in vitro model, we culture CD4+ or CD8+ T cells from two T cell receptor transgenic mice strains together with human MSCs, followed by flow cytometry analysis of different activation markers present on T cells, real time RT-PCR for important transcription factors and ELISA for Th1 and Th2 cytokines. First, proliferation of both CD4+ and CD8+ T cells is clearly inhibited by human MSCs. These T cell subsets are, with some exceptions, similarly affected by MSCs. Both CD25 and CD69 activation markers are significantly inhibited on the surface of CD4+ and CD8+ T cells. Second, factors associated with a T regulatory phenotype (CTLA-4, CD62L) have an increased expression, while IFN-gamma and other cytokines are inhibited by MSCs in both T cell subsets. Third, real time RT-PCR data analysis showed that transcription factors Tbet and GATA3 are significantly inhibited by MSCs. Also, MSCs induce a slight increase in annexin V positive CD4+ T cells, but have no effect on the viability of CD8+ T cells. Moreover, the effects seem to be specific to MSCs; incubating the T cells with two different controls has no effect on T cell proliferation and activation.
Identification and characterization of myeloid-derived suppressor cells in neonates (147.8)
Authors: Jacobson Amanda , Mitchell Caroline , Xu Min , Frenkel Lisa , Horton Helen 
Published: January 2023

Abstract
The neonatal immune system is regarded as immature and consists of impaired T cell and antigen presenting cell function. During pregnancy, suppression of both the maternal and fetal immune responses is necessary to allow successful viviparity. The neonatal immune response may have to overcome this modulated immune environment in the first months of life in order to respond at the level required for protection. It is unclear whether infant immune responses are simply immature or are being actively suppressed. The primary goal of this study was to elucidate mechanisms of infant immune deficiencies, in particular those that are present at birth. We have identified a prevalent population of arginase 1-positive myeloid-derived suppressor cells (MDSC) within neonates (7.7%+/-6.9% of cord blood vs 0.7%+/-0.5% of adult blood mononuclear cells) that may negatively influence infant immune responses. This cell population present at birth has not previously been described in infants, but similar cells have been described to suppress T cell responses in adult cancer patients. In addition, we demonstrate that neonatal MDSC are functional and suppress allogeneic T cell proliferative responses in an arginase 1-dependent manner by an average of 38%. These data suggest that suppressor cell populations, like MDSC, can suppress infant T cell responses. This may be one mechanism behind reduced neonatal immunity resulting in inefficient responses to both infection and vaccination early in life.
CD38 involvement in autoimmune disease using a murine model for systemic lupus erythematosus (148.13)
Authors: Romero-Ramirez Hector , Gaxiola-Centeno Ricardo , Santos-Argumedo Leopoldo , Rodriguez-Alba Juan Carlos 
Published: January 2023

Abstract
Mouse models contribute in our understanding of human diseases. By this way, several strains of systemic lupus erythematosus (SLE)-prone mice including New Zealand Black (NZB), F1 hybrids of NZB x New Zealand White (NZW) (B/W F1), MRL/Mp-lpr/lpr (MRL/lpr), and BXSB mice are important in the research of the autoimmune diseases. Several genes and signaling pathways molecules have been related with SLE pathologies such as: Lyn, CD22, SHP-1 or the sle1, sle2 and sle3 congenic models. CD38 is a transmembrane receptor able to induce activation, proliferation, and survival of human and mouse lymphocytes; this molecule is expressed along the B cell ontogeny, in addition, CD38 is an ectoenzyme involved cell adhesion and is used as a disease marker for leukemia and myeloma, also is a dependable negative prognostic marker for chronic lymphocytic leukemia (CLL). The function of CD38 in autoimmunity has been proposed in human but there are not reports that clear the authentic role of this molecule in SLE. To study the implication of CD38 in the SLE pathogenesis we compare the proteinuria, serum ANA and anti-dsDNA antibody production, body-weight, nephritis and mortality in the CD38-deficient compared to the wild type (WT) mice. Subsequently, we expect that the pathologic manifestations of nephritis appear significantly earlier in the WT mouse as well survival rate changes.
AID dysregulation in lupus-prone MRL/Faslpr/lpr mice promotes interchromosomal c-Myc/IgH loci translocations, increased class switch DNA recombination and production of anti-dsDNA IgG autoantibodies: modulation by HoxC4 (148.25)
Authors: White Clayton , Hawkins J. , Pone Egest , Al-Qahtani Ahmed , Mai Thach , Zan Hong , Casali Paolo 
Published: January 2023

Abstract
Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR), which are critical in the generation of pathogenic autoantibodies. In these studies, we addressed the regulation of AID by HoxC4 in lupus. We found that SLE patients and lupus-prone MRL/Faslpr/lpr mice displayed increased expression of HoxC4, which directly activates the promoter of the AID gene, and increased expression of AID. Dysregulation of these proteins was associated with increased CSR in B cells of MRL/Faslpr/lpr mice. In the HoxC4-/- MRL/Faslpr/lpr mice we generated, HoxC4-deficiency resulted in reduced AID expression, impaired CSR and decreased serum anti-dsDNA IgG, particularly IgG2a production, in association with a reduction in IgG deposition in kidney glomeruli. Consistent with our previous findings that upregulated AID expression is associated with extensive DNA lesions, we found a high frequency of c-Myc to IgH translocations in MRL/Faslpr/lpr mice. The frequency of c-Myc to IgH translocations was significantly reduced in autoimmune MRL/Faslpr/lpr mice deficient in HoxC4. Our findings showed that HoxC4 is upregulated in lupus B cells, and this plays a major role in dysregulating AID expression, increasing CSR and autoantibody production, and promoting c-Myc to IgH translocations.
Lovastatin exhibits synergy with Vitamin D hormone to confer protection from experimental autoimmune encephalomylitis (148.5)
Authors: Paintlia Ajaib , Paintlia Manjeet , Singh Avtar , Singh Inderjit 
Published: January 2023

Abstract
Recent studies provide sufficient evidence that disease modifying agents (DMAs) i.e., vitamin D hormone (VDH) and statin (lovastatin) were immunomodulatory to attenuate experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Interestingly, irrespective of their different mechanism of action these DMAs produce similar protective activities to attenuate EAE. Therefore, we asked whether statin regulate the vitamin D precursor (VDP; vitamin D3) homeostasis in treated EAE model. Interestingly, we observed a significant increase in the serum level of both VDP and VDH in lovastatin treated EAE animals as compared to those treated with vehicle. It was associated with diminished level of CYP24A1 (VDH inactivating enzyme) and elevated level of CYP27B1 (VDH synthesizing enzyme) involved in VDH metabolism in the blood cells and spinal cord of EAE treated with lovastatin than vehicle. Next, we tested the potential of lovastatin and VDH in combination to confer protection from EAE. Interestingly, suboptimal doses of these DMAs significantly attenuated acute clinical exacerbations, cellular infiltration, inflammatory response, axonal loss and demyelination in the spinal cord of EAE animals compared with their individual treatment analyzed by using quantitative and qualitative analyses. Altogether, these findings provide initial evidence that lovastatin maintains VDH homeostasis and its synergy with VDH enhances neuroprotection in EAE/MS brain.
CXCL10 is an important therapeutic target to treat bone metastasis (149.18)
Authors: Lee Zang Hee , Lee Jong-Ho , Ha Hyunil 
Published: January 2023

Abstract
CXCL10 is a chemokine, which takes a significant role in migration and proliferation of T cells. It binds to the receptor CXCR3 and is induced in a wide variety of cell types. We have reported in our previous study that RANKL promotes the expression of CXCL10 in osteoclast precursors and, in turn, CXCL10 mediates RANKL expression in T cells in the synovium. Auto-amplification loop of CXCL10 has been acknowledged to be involved in bone destruction of rheumatoid arthritis. However, the role of CXCL10 in bone metastatic destruction remains largely unknown. We are currently conducting further research on the potential role of CXCL10 in bone resorption and bone metastasis. In this study, the synergistic production of CXCL10 was found in co-culture of bone marrow cells and cancer cells in the presence of RANKL. In addition, the serum level of CXCL10 was increased in bone metastatic mice. The CXCL10 deficient mice showed less metastatic lesions in long bone compared to wild mice. Furthermore, treatment with neutralizing antibody to CXCL10 and antagonist for CXCL10 and CXCR3 interaction significantly inhibited the infiltration of tumor cells into long bone and increased the mice survival rate. Therefore, CXCL10 might be an important therapeutic target in the prevention of bone destruction in bone metastasis.