bluuebunny/crossref_metadata_2025_split huggingface dataset:
The alternative complement system and obesity: using knockout mouse models to investigate fat metabolism (96.24)
Authors: Cianflone Katherine , Paglialunga Sabina , Roy Christian , Lu HuiLing , Pekna Marcela 
Published: January 2023

Abstract
A growing body of evidence now links immunology and metabolic functions. The alternative system plays a role in injury and tissue damage as assessed by complement 3 knockout (C3KO), factor B (FBKO) and factor D (FDKO) mice with injury and septic shock. Recently the C5L2 receptor was found to act as a decoy receptor for C5a during similar conditions. Acylation stimulating protein (C3adesArg/ASP), a by-product of the alternative complement pathway also acts via C5L2 to stimulate triglyceride (TG) synthesis in adipose tissue.
Wildtype (WT), C3KO, FBKO and C5L2KO mice on a normal chow diet were studied over 12 weeks. No difference in body weight was observed between KO and WT mice. However C3KO, FBKO and C5L2KO mice displayed increased food intake by 56%, 48% and 62% respectively vs. WT mice (p&lt;0.05). Consistent with previous findings, C3KO mice showed delayed TG clearance during a fat load. FBKO and C5L2KO mice also display delayed postprandial lipemia. Adipose tissue from C5L2KO mice showed reduced ex vivo TG synthesis (-83%, p&lt;0.001). Also, DGAT (TG synthesis enzyme) activity and protein were significantly reduced in C3KO mice vs. WT.
Therefore, under normal physiological, alternative complement KO mice display altered fat metabolism. We attribute this phenotype to the lack of ASP and C5L2 signalling, however, further investigation is still required to understand the association between immunity and metabolism.
Funding: CIHR and NSERC
Effect of Dermatophagoides pteronyssinus on expression of monocyte chemotactic protein 1 (MCP-1)/IL-6/IL-8 in the human monocytic cell line, THP-1 (96.26)
Authors: Lee Ji-Sook , Kim In Sik , Kim Dong Hee , Kim Joo-Hwan , Jeong Hye Gwang , Ryu Ji-Sun , Choi Hye-Jin , Yun Chi-Young 
Published: January 2023

Abstract
RATIONALE: The house dust mite, Dermatophagoides pteronyssinus (DP) is a major source of allergens implicated in the pathogenesis of allergic disorders; they include asthma, allergic rhinitis, and atopic dermatitis. Monocyte chemotactic protein 1 (MCP-1/CCL2)/IL-6/IL-8 plays a pivotal role in mediating the infiltration of various cells into the skin of atopic dermatitis and psoriasis.
METHODS: The aim of this study was to investigate the effect of DP extract (DpE) on expression of MCP-1/IL-6/IL-8 mRNA and protein and the signal transduction leading to MCP-1/IL-6/IL-8 expression induced by DpE in the human monocytic cell line, THP-1. The mRNA and protein expression of MCP-1/IL-6/IL-8 was measured by performing RT-PCR and ELISA.
RESULTS: DpE-stimulated cells showed elevated MCP-1/IL-6/IL-8 expression in a time and dose-dependent course. MCP-1/IL-6/IL-8 expression induced by DpE is strongly inhibited by PP2, an inhibitor of Src, rottlerin, an inhibitor of protein kinase C δ (PKC δ) PD98059, an inhibitor of MEK and SB202190, an inhibitor of p38 mitogen-activated protein kinase (MAPK).
CONCLUSIONS: These results indicate that DP increases MCP-1/IL-6/IL-8 expression and transduces the signal through extracellular signal-regulated kinases (ERK1/2) in human monocytes.
STAT3 mediates the initiation and progression of Lyme carditis (96.29)
Authors: Zegarra-Moro Ofelia L , Vinasco Javier , Braga Walter U , Moro Manuel H 
Published: January 2023

Abstract
Lyme disease is caused by Borrelia burgdorferi and represents a worldwide public health problem. This multisystemic and chronic disease may affect several organs including the heart. However, little is known about the molecular mechanisms that control and/or facilitate the development of Lyme carditis. Signal transducer and activator of transcription 3 (STAT3) is critical in mediating cytokine signaling and it has been involved in diverse pathological processes and also implicated in a variety of immune responses. The aim of this study is to examine the role of STAT3 in the initiation and progression of Lyme carditis using a murine model. Six week-old C3H and BALB/c mice were inoculated with B. burgdorferi. Hearts were excised at defined time intervals that reflected the progression of Lyme disease in the mouse model: 7, 14, 21, 30, and 60 days post-inoculation. Infected cardiac tissues were screened for expression of STAT3 and STAT3-regulated proteins by Western blot analyses, immnunoprecipitation and immunofluorescence studies. We show that STAT3, pSTAT3 and STAT3 regulated proteins were upregulated in cardiac tissues infected with B. burgdorferi. Furthermore, we found a direct correlation between upregulation of STAT3/pSTAT3 and progression of the disease during the acute phase of Lyme carditis. Our results suggest that STAT3 plays a key role in Lyme carditis and may represent a molecular target for monitoring the initiation and progression of Lyme carditis. NIH P20RR016443-04 .
HIV-1 infection alters cytokine and chemokine networks that influence innate immunity in the lung (96.9)
Authors: Nicol Marlynne Quigg , Hayete Boris , Pereira Albertina , Rarick Matt , Mathys Jean-Marie , Collins James , Skolnik Paul 
Published: January 2023

Abstract
Objective: To create mathematical network models of cytokine and chemokine interactions in the lungs of HIV+ subjects, utilizing protein and mRNA measurements, to better elucidate the relative importance of elements within these complex networks.
Methods: We used U937, U1 (HIV-1-infected) cell lines, alveolar macrophages from HIV+ subjects and matched healthy controls, exposed to LPS and cytokines. We measured cytokine/chemokine protein production by Luminex, and mRNA by real-time PCR, for nine moieties. Using these perturbations and NIR algorithms, functional relationship maps were constructed.
Results: Analysis of protein or mRNA data showed differences in type and magnitude of responses in infected cells. Clear differences in connectivity between the infected and uninfected cell lines for the nine moieties were also apparent in functional relationship maps derived from the protein or mRNA data. In addition, concordance of mRNA maps with maps produced from microarray data validated our network hypothesis.
Conclusions: Preliminary network models show the feasibility of obtaining biologically relevant results that model cytokine and chemokine networks in the lung, rather than individual moieties or single agonist/antagonist pairs. These networks may indicate connections not previously considered important in HIV-1 pathogenesis in the lung.
Supported by NIH grant R01HL076114
Loss of Mac-1 expression in mice leads to more severe forms of inflammatory disease in both the MRL/MpJ-Faslpr and CIA Models (97.1)
Authors: Bullard Daniel C , He Xiaodong , Schoeb Trenton R , Raman Chander 
Published: January 2023

Abstract
Mac-1 plays key roles in innate immune responses, and has also been implicated in the pathogenesis of diseases such as SLE and RA. Previously, we observed that Mac-1 deficiency in MRL/MpJ-Faslprmice, a model for SLE, resulted in a more severe inflammatory phenotype. To further examine mechanisms by which this adhesion molecule regulates inflammation in this model, we investigated whether loss of Mac-1 specifically altered T cell activation. We found that both Mac-1 deficient CD4+ and CD8+ T cells showed a hyperproliferative response following stimulation with low doses of anti-CD3 compared to control cells. We also analyzed T cell proliferation kinetics in Mac-1 deficient DO11.10 TCR transgenic T cells in response to Ova-peptide challenge and observed a similar hyperproliferation phenotype, suggesting that this adhesion molecule can negatively regulate T cell proliferation, independent of Faslpr gene expression. Finally, we analyzed Mac-1 deficient mice in the CIA model of RA to determine whether loss of expression of this adhesion molecule would also lead to a more severe inflammatory phenotype. We observed that Mac-1 deficient mice showed an accelerated onset of joint inflammation compared to wild type controls. Thus, these results suggest that Mac-1 can act as a negative regulator in the development of inflammatory diseases, possibly through controlling T cell activation and proliferation.
ICAM-1 expression is required for regulatory T cell localization in the lungs of M. tuberculosis infected mice (97.2)
Authors: Plessner Hillarie L. , Flynn JoAnne L. 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) is a widespread human pathogen that persists in the lung of latently infected individuals. Control over Mtb infection relies upon migration of leukocytes into the granuloma. We hypothesized that the adhesion molecule ICAM-1 plays a role in the migration, retention and interaction of leukocytes during Mtb infection. While previous studies in ICAM-1−/− mice have indicated that ICAM-1 is required for long-term control over Mtb infection, the mechanism remains unclear. In this study, ICAM-1−/− mice infected with Mtb survived over 10 months post-infection and controlled bacterial burden. Although granuloma formation appeared normal, higher overall cell numbers were observed by H&E staining and flow cytometry. We observed inhibited T cell contraction in the absence of ICAM-1 following primary Mtb infection. T regulatory cells were significantly reduced in ICAM-1−/− mice, which could play a role on T cell contraction. We conclude that ICAM-1 expression helps to control lung pathology by supporting T regulatory cells. Future studies will attempt to elucidate the mechanism by which ICAM-1 affects T regulatory cell recruitment to or retention in the lungs.
STAT6 is a novel regulator of CD44 expression in human B cells (97.4)
Authors: Mishra Jyoti Prasad , Mishra Sasmita , Kumar Ashok 
Published: January 2023

Abstract
Interactions of CD44, an adhesion molecule, with its ligand, hyaluronan (HA) play a crucial role in cell migration, inflammation and immune response. The regulation of CD44 expression particularly in human B cells is not well understood. We have previously demonstrated that CD44 expression in human monocytic cells is regulated by Egr-1 and AP-1 transcription factors (Mishra et al. 2005, JBC). IL-4, a pleotropic cytokine is known to regulate CD44-HA interactions, cell migration, and differentiation of human B cells. To understand the regulation of IL-4-induced CD44 expression in human B cells, we used an EBV-transformed Burkitt’s lymphoma cell line, BL30/B95-8 as a model system. Our results suggested that IL-4 did not induce the expression of Egr-1 and AP-1 as determined by Northern and Western blot analysis and gel shift assays. To elucidate the transcription factors involved, we demonstrated by promoter analysis and gel shift assays that STAT-6 plays a critical role in IL-4-induced CD44 regulation in human B cells. We also investigated the upstream signaling events and demonstrated that IL-4-induced STAT-6 is activated by two distinct signaling pathways namely Jak-1/3 and ERK-MAPK and is independent of the IRS2/PI3 kinase pathway. Taken together, our results suggest a novel pathway of CD44 regulation involving the activation of STAT-6 through the upstream Jak-1/3 and ERK-MAPK in IL-4-stimulated human B cells.
Immobilized SDF-1α Triggers Rapid VLA-4 Affinity Increases to Stabilize Lymphocyte Tethers on VCAM-1 and Subsequently Initiate Firm Adhesion (97.7)
Authors: Lawrence Michael Brandeau , Divietro Jeffrey A. , Larson Richard S. , Sklar Larry A. 
Published: January 2023

Abstract
The integrin VLA-4 (?4?1) mediates tethering and rolling events as well as firm adhesion of leukocytes to VCAM-1. Unlike selectins, VLA-4 integrin-mediated lymphocyte adhesiveness can be modulated by chemokines through intracellular signaling pathways. To investigate the effects of the chemokine Stromal cell Derived Factor-1? (SDF-1?) on VLA-4-mediated lymphocyte adhesion; human peripheral blood lymphocytes (PBL) were flowed over VCAM-1 substrates in a parallel plate flow chamber with surface immobilized SDF-1?, a potent activator of firm adhesion. The initial tethering interactions had a median lifetime of 200 ms, consistent with the half-life of low affinity VLA-4-VCAM-1 bonds. Immobilized SDF-1? acted within the lifetime of a primary tether to stabilize initial tethering interactions, increasing the likelihood a PBL would remain interacting with the surface. As expected, the immobilized SDF-1? also increased the ratio of PBL firm adhesion to rolling. An LDV peptide-based small molecule that preferentially binds high affinity VLA-4 reduced PBL firm adhesion to VCAM-1 by 90%. The reduction in firm adhesion due to blockage of high affinity VLA-4 was paralleled by a four-fold increase in the fraction of rolling PBL. SDF-1? activation of PBL firm adhesion on VCAM-1 depended on induction of high affinity VLA-4 rather than recruitment of a pre-existing pool of high affinity VLA-4 as previously thought.
Supported by NIH R01 HL54614.
Cloning and Expression of Bovine CCL28 (98.10)
Authors: Hughes Melissa , Martino Ben , Voyich Jovanka , Wilson Eric 
Published: January 2023

Abstract
Chemokines play a vital role in mediating leukocyte homing and accumulation to tissues. The chemokine CCL28 also known as Mucosal Epithelial Chemokine (MEC) has been shown to be essential in mediating migration of IgA antibody secreting cells to the lactating mammary gland and gastrointestinal tract. This protein has also been shown to function as an antimicrobial peptide. Cows and other ruminants do not transfer antibody transplacentally as do humans and mice. Therefore efficient transfer of immunity to the suckling newborn in ruminants is highly dependant on efficient transfer of antibodies via colostrum. Neither the role of CCL28 in the transfer of immunity from mother to nursing neonate, nor the role of CCL28 as a potential antimicrobial compound in milk has yet been elucidated in the cow. To begin addressing these basic questions we are cloning and expressing bovine CCL28. Using a putative bovine sequence of CCL28 from GenBank and known sequences from mouse and human CCL28, appropriate primers with restriction sites were created for bovine CCL28. Salivary gland mRNA was collected and RT-PCR was employed to amplify the coding region of the gene. The amplified fragment was sequenced to establish concordance with GenBank records. The coding region was then inserted into a pMAL-c2G vector and is being used to generate recombinant bovine CCL28.
The key role of a G protein coupled receptor mFPR2 in the development of inflammatory airway disease (98.4)
Authors: Wang Ji Ming , Li Yingying , Hu Jinyue , Huang Jian , Gong Wanghua , Chen Keqiang 
Published: January 2023

Abstract
The human G protein-coupled formylpeptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate leukocyte chemotaxis in response to a variety of chemotactic peptides associated with inflammation and bacterial infection. In order to ascertain the role of this receptor in innate host defense, we generated mFPR2 knockout (mFPR2−/−) mice. mFPR2−/− mice developed normally, but with reduced number of myeloid cells in the bone marrow. In pulmonary allergic inflammation induced by ovalbumin (OVA), mFPR2−/− mice showed markedly reduced myeloid cell exudation in the broncho-alveolar lavage (BAL) and cell infiltration in the lung tissue, in association with impaired epithelial proliferative responses. In addition, the BAL from OVA-treated wild type mice contained high levels of mFPR2 specific chemotactic activity, which was absent in the BAL of mFPR2 −/− mice. Our results indicate a key role for mFPR2 in the development of inflammation in the allergic airway disease.
This project has been funded with federal funds from the National Cancer Institutes, National Institutes of Health, under Contract No. NO1-CO-12400 and was also supported in part by the Intramural Research Program of the NCI, NIH.
CX3CR1 deficiency impairs the recruitment of dendritic cells to the arterial intima and reduces atherosclerotic burden (98.7)
Authors: Liu Peng , Spencer Jessica A , Johnson Ashley E , Patel Dhavalkumar D 
Published: January 2023

Abstract
Dendritic cells (DCs) have recently been found in atherosclerosis-predisposed regions of arteries and have been proposed to be causal in atherosclerosis. Our previous studies demonstrated that the chemokine receptor CX3CR1 is associated with arterial injury and atherosclerosis. Here we investigated if DC arterial accumulation was correlated with atherosclerosis and the mechanisms by which CX3CR1 may play a role. Mouse aortas were isolated and subjected to en face immunofluorescence analysis. We found that DCs were located predominantly in the intimal regions of arterial branch points and curvature. Consistent with the increased accumulation of intimal DCs in aging (2196.2±154) and ApoE−/−aortas (2697.5±214.3) compared to young WT aortas (904±79.5, p=0.004 and 0.05 respectively), the incidence of atherosclerosis was 88.9% for aging and 100% for ApoE−/− mice. CX3CR1 was expressed on intimal DCs, and DC numbers were decreased in CX3CR1−/− aortas (541.1±93.6 vs. 904±79.5 for WT, p=0.0008). CX3CR1-deficiency decreased atherosclerosis in aortas of ApoE−/−mice by 71% (0.41%±0.11% of aorta surface for ApoE−/−/CX3CR1−/− vs. 1.39%±0.02% for ApoE−/−, p=0.00006). Thus, the accumulation of intimal DC increases in aging and ApoE−/− aortas and correlates with the generation of atherosclerosis. CX3CR1-deficiency impairs the recruitment of DC to the aortic wall and markedly reduces the atherosclerotic burden.
Mechanisms involved in accumulation of host cells within the CNS during adoptive transfer induced EAE (99.10)
Authors: Lees Jason R , Russell John H 
Published: January 2023

Abstract
Adoptive transfer of activated central nervous system (CNS) antigen specific T-cells into susceptible strains of mice results in the invasion of transferred cells into the CNS. CNS invasion by these initiating T-cells and recruited monocytes culminates in the induction of experimental autoimmune encephalomyelitis (EAE). Following this initial invasion a secondary infiltrate of host T-cells of unknown function and antigenic specificity enters the CNS. The role of these secondary-infiltrating cells in the initiation, development, and resolution of EAE remains uncharacterized. In this study we utilized an adoptive transfer model of EAE induction in mice to characterize the mechanisms involved in entry of host T-cells found within the CNS following disease initiation. These cells were further examined for both phenotypic and functional characteristics at various times after disease initiation. Finally, we examined the necessity for antigenic recognition of peptides in entry and retention of cells within the CNS. Findings from this study allow us to characterize the mechanisms involved in accumulation of host cells within the CNS during EAE pathogenesis.
Plexin-A1 on dendritic cells and its interaction with a T cell surface molecule (B11)
Authors: Eun So-Young , O’Connor Brian Patrick , Wong Athena W , Ye Zhengmao , Ting Jenny P.-Y. 
Published: January 2023

Abstract
Plexin-A1 was first discovered on neurons and found to cause growth cone collapse in response to semaphorin3A, a repelling cue. Interestingly, we and others have recently observed that plexin-A1 is also an important factor for the interaction between antigen-presenting cells and T cells (Wong, A. W., et al. 2003, Nat. Immunol.; Takegahara, N., et al. 2006, Nat. Cell Biol.). Plexin-A1 on dendritic cells is shown to play a significant role in fully activating antigen-specific T cells in their co-culture. Effect of plexin-A1 on T cell activation is shown to be signaled through the Rho GTPase to accumulate actin filaments toward immune synapse (Eun, S.-Y., et al., 2006, J. Immunol.). Our group and others have identified a ligand for plexin-A1 on T cells as the semaphorin6D molecule, which is upregulated on activated T cells. In the co-culture of DCs and T cells, we observed that T cell proliferation became significantly reduced by intervention of soluble sema6D fusion protein conjugated with human IgG. Signaling events in T cell activation were also blocked by reduced interaction of sema6D with plexin-A1. These findings suggest that interaction of plexin-A1 and sema6D mediates activation signals for both DCs and T cells.
(This work is supported by National Institutes of Health Grant AI29564).
Role of human skin resident T cells in wound healing (B116)
Authors: toulon antoine , Bhavsar Dhaval , Tenenhaus Mayer , Pineau Nathalie , Lionel Breton , Jameson Julie , Havran Wendy Lynn 
Published: January 2023

Abstract
Cutaneous wound healing is a complex process requiring constant communication between cells in the form of cytokine release, cell-to-cell contacts and cell-to matrix interactions. Skin gammadelta T cells have been shown to play unique roles in tissue homeostasis and during tissue repair through local secretion of distinct growth factors in mice. However, because the distribution of resident T cells (gamma delta vs alpha beta) is different in mice and humans we aimed to characterize the role of epithelial resident T cells in wound repair in humans. In the present study we show that the freshly isolated Vdelta1 gamma delta and alpha beta resident T cells secrete IGF-1 after stimulation by PMA and ionomycin. Interestingly both cell types are activated in acute wounds and secrete IGF-1 to promote wound healing. The characterization of the functional activity of resident T lymphocytes in acute wounds should allow the development of new therapeutic strategies against chronic wounds.
Supported by grants from L’Oreal, NIH and Fondation pour la Recherche Médicale.
Nature of Bacterial Provocation Determines Susceptibility To Colitis (B117)
Authors: Henderson Abigail Lynn , Jergens Albert , Liu Zhiping , Hostetter Jesse , Dorn Andrea , Wannemuehler Michael 
Published: January 2023

Abstract
Development of inflammatory bowel disease (IBD) involves predisposing and triggering events including aberrant immune responses against microbial antigens. Colonization of defined flora (DF) mice with Helicobacter bilis has been shown to induce immune responses to the resident flora.
Aim: To determine the mechanisms underpinning susceptibility to colitis after colonizing DF mice with new bacterial species.
Methods: Following colonization of DF mice with H. bilis or Escherichia coli, mice were treated with a low dose (1.5 %) of dextran sulfate sodium (DSS) (i.e., inflammatory trigger). Following euthanization, severity of colonic lesions were assessed as well as flora-specific antibody and T cell responses.
Results: Colonization of DF mice with H. bilis, unlike E. coli, significantly (p&lt;0.05) increased the severity of DSS-induced colitis. T cells from mice colonized with H. bilis and E. coli displayed in vitro ASF-specific recall responses but only the responses from the H. bilis-infected mice correlated with severity of lesions. T cell responses from E. coli-colonized mice produced more ASF-specific IL-10 than those from H. bilis colonized mice.
Implications: These studies indicate that bacterial colonization can perturb mucosal homeostasis by impairing mucosal regulatory function(s) and exacerbate host susceptibility to subsequent colitic insults resulting in IBD.
Supported by F31DK070563-01A2.