bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-1 signaling contributes to the chronic inflammatory response to the oral pathogen, P. gingivalis (169.17)
Authors: Weinberg Ellen , Kramer Carolyn , Beaulieu Lea , Orlowski Anthony , Morgan Elise , Freedman Jane , Genco Caroline 
Published: January 2023

Abstract
Objective. Interleukin-1 signaling is an important mediator of the pro-inflammatory response to pathogens. We have shown that the oral pathogen P. gingivalis (Pg) induces the release of IL-1alpha (IL-1α) and IL-1beta (IL-1β) in cultured cells in vitro and is associated with chronic inflammation including platelet activation, oral bone loss and atherosclerosis. We sought to define the specificity (IL-1α vs. IL-1β) of IL-1 receptor signaling on platelet function and oral bone loss in response to Pg. Methods. Wild type (WT), IL-1β knockout (IL-1β KO), and IL-1 receptor knockout (IL1R KO) mice were challenged orally with Pg or control (Con) 3 times/week for one week. Platelet activation (flow cytometry) was determined one day (acute, N=3/group) and 6 weeks (chronic, N=5/group) after the third Pg challenge. Oral bone loss (micro-CT analysis) was determined 6 weeks after the third Pg challenge (N=5/group). Results. Challenge with Pg resulted in significant platelet activation in acute and chronic samples in WT but not in IL-1β KO or IL1R KO mice. Challenge with Pg resulted in significant oral bone loss in WT mice. Inflammatory bone loss was prevented in IL-1R KO mice but was not prevented in IL-1β KO mice. Conclusions. Platelet activation following Pg challenge is likely mediated by Pg-induced IL-1β release and signaling. In contrast, oral bone loss does not appear to be mediated by IL-1β and may involve Pg-induced IL-1α release and signaling through IL1R.
Cellular mechanisms linking pattern recognition and autophagy in Dictyostelieum discoideum (169.19)
Authors: Snyder Michelle , Pflaum Katherine , Gerdes Kimberly , Yovo Kossi 
Published: January 2023

Abstract
Pattern recognition machinery is used by cells of the innate immune system to detect conserved patterns on invading pathogens. Dictyostelieum discoideum is a model organism that phagocytizes bacteria for nutritional purposes, and we have shown recently that D. discoideum may use conserved pattern recognition machinery to detect and respond to their bacterial prey, since D. discoideum cells stimulated with the microbial pattern lipopolysaccharide (LPS) more efficiently clear phagocytized bacteria. Here we extend these findings, showing that LPS stimulates maturation of autophagosomes and transport of autophagosomal contents to lysosomes in D. discoideum cells exposed to Staphylococcus aureus. Induction of autophagy appears sufficient for increased bacterial killing in D. discoideum cells, as D. discoideum clears bacteria at in increased rate when cells are treated with the autophagy-inducing drug, rapamycin. Finally, we illustrate that LPS-enhanced transport of phagocytized S. aureus to the degradative lysosomes is significantly reduced in D. discoideum cells lacking the autophagy-related protein Atg1 or the toll/interleukin-1 receptor domain-containing protein TirA. Thus, for the first time, we link microbial pattern recognition and autophagy in this model organism, providing greater understanding of the highly conserved mechanisms underlying pathogen detection.
Ifitm proteins are required for appropriate localization and function of membrane proteins following type I interferon activation (169.2)
Authors: Wee Yin Shen , Roundy Kirstin , Weis Janis , Weis John 
Published: January 2023

Abstract
The innate immune response Interferon-inducible transmembrane (Ifitm) proteins have been characterized as influencing immune cellular proliferation, aiding signaling complexes and restricting virus infections following interferon activation although a specific functional mechanism for the Ifitm proteins has not been described. We have analyzed the function(s) of these proteins in the mouse by comparing the localization of known membrane endocytic constituents between cells obtained from wild type (WT) mice and mice lacking the five Ifitm genes (IfitmDel). Cells obtained from IfitmDel mice and treated with IFNβ demonstrated a loss of clathrin from the surface of cells, compared to WT, and a loss of clathrin-mediated endocytosis. The pH of endosomes of cells obtained from the IfitmDel, with or without interferon activation, was also altered (more basic) suggesting the localization and/or function of the vacuolar ATPase proton pumps in such cells was altered by the loss of the Ifitm proteins. Co-immunoprecipation of Ifitm proteins with the proton-transporter complex constituent Atp6v0b demonstrated a direct interaction between the Ifitm proteins and the vacuolar ATPase’s. These data, in total, suggest that the Ifitm proteins serve as protein complex organizers and function to maintain the appropriate cellular localization and function of membrane proteins following type I interferon activation.
Caspase-1 is hepatoprotective through up-regulation of autophagy after hemorrhagic shock (169.20)
Authors: Sun Qian , Billiar Timothy , Scott Melanie 
Published: January 2023

Abstract
Hemorrhagic shock induces tissue hypoxia, cellular oxidative stress and production of reactive oxygen species, which we have previously shown leads to activation of the inflammasome and caspase-1. Our previous data also show that caspase-1 is hepatoprotective after hemorrhagic shock/resuscitation (HS/R). Autophagy is a protective response to cellular stress and we hypothesized that caspase-1 is hepatoprotective by regulating autophagy after HS/R. Autophagic markers beclin1 were upregulated in WT liver after HS/R but to significantly lower levels in caspase-1-/- liver, and caspase-1-/- liver also had higher levels of apoptosis. Adenovirus encoding beclin1 (Adbeclin1) or control AdGFP was injected via tail vein in WT and caspase-1-/- mice. After 48h mice were subjected to HS/R. Immunoblotting of whole liver lysates confirmed beclin1 overexpression after Adbeclin1. Caspase-1-/- mice expressing Adbeclin1 had significantly less liver injury after HS/R and lower cytochrome c release (marker of apoptosis/mitochondrial damage) compared with AdGFP-caspase-1-/- mice and similar to WT levels. Similarly, in vitro primary hepatocytes isolated from caspase-1 -/- mice had decreased beclin1 expression, reduced autophagic flux and increased cells death after hypoxia/reoxygenation compared with WT cells. Together our data suggest that upregulation of beclin1 is vital for hepatoprotection after HS/R and that caspase-1 regulates beclin1 expression and autophagy through a novel pathway.
Critical role of TLR4 in human metapneumovirus mediated innate immune responses and disease pathogenesis (169.21)
Authors: Kolli Deepthi , Velayutham Thangam , Garofalo Roberto , Casola Antonella 
Published: January 2023

Abstract
Human metapneumovirus (hMPV), described for the first time in 2001, has become one of the main viral pathogens responsible for acute respiratory tract infections in children, elderly and immunocompromised patients. The mammalian Toll-like receptors (TLR) were identified as critical regulators of innate immunity to a variety of microbes, including bacteria and fungi. Respiratory syncytial virus (RSV) fusion protein has been shown to activate TLR4, but their role in other viral infections, such as hMPV, has been largely unexplored. In this study, we examine the in vivo innate immune response in TLR4-deficient (C57BL/10ScNJ) mice and wild-type (C57BL/10SnSnJ) mice challenged with hMPV virus to address the role of TLR4 in the innate immune response to this respiratory virus infection. Our results demonstrate that mice lacking TLR4 loose less body weight compared to wild type mice. When inflammatory mediators was measured in bronchoalveolar lavage at different days post-infection, significantly lower levels of proinflammatory cytokines (IL-6, TNF-α) immunomodulatory cytokines (IL-12 p40, IL-17) and chemokines (MCP-1, MIP-1α) were detected. Further, consistent with bodyweight loss, TLR4 deficient mice show better pulmonary function demonstrated by reduced airway obstruction and airway hyperresponsiveness. The results of this study indicate that TLR4 is important for activation of the innate immune response to hMPV infection however it can also contribute to disease pathogenesis.
Expression of non-classical HLA molecule, HLA-E during Japanese encephalitis virus (JEV) infection (170.13)
Authors: Verma Shwetank , Kim Kwang , Carbone Ennio , Manjunath Ramanathapuram 
Published: January 2023

Abstract
Endothelial cells play an important role in transmission of JEV across the blood brain barrier while fibroblasts are involved in peripheral spread of infection. JEV, a neurotropic flavivirus was found to replicate and establish productive infection in human endothelial cell lines leading to production of IFN-β and TNF-α. Expression of HLA-E mRNA and protein showed significant upregulation during JEV infection of the human endothelial cell line, ECV304, human brain microvascular endothelial cells (HBMECs) and a primary human foreskin fibroblast (HFF) cell line. This is the first report to show that the infection of endothelial cells by JEV can result in the release of HLA-E as soluble molecules which is mediated by matrix metalloproteinases. However, HFF cells showed only upregulation of HLA-E on cell surface upon JEV infection. Experiments using inhibitors of MAPK and NF-κB suggest that the release of soluble HLA-E upon JEV infection was dependent on the MAPK pathway but independent of NF-kB. The soluble HLA-E that was released upon JEV infection was functionally active since it inhibited the IL-2 and PMA induced phosphorylation of ERK1/2 in NK cell lines. Inhibition of ERK1/2 phosphorylation has been shown to inhibit cytotoxicity of NK cells by inhibiting mobilization of granzyme granules to immunological synapse. Thus, it is possible that release of soluble HLA-E can have far reaching consequences on activation of NK cells as well as CTLs upon JEV infection.
Expression of suppressor of cytokine signaling 1 (SOCS1) impairs immune defense against influenza infection. (170.24)
Authors: Sun Keer , Metzger Dennis 
Published: January 2023

Abstract
Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. Of interest, Influenza infection induces high levels of SOCS1 in airway immune cells. We have now found that Socs1-/-IFN-γ-/- mice exhibited increased resistance to influenza infection as shown by improved viral clearance and survival rate compared to both IFN-γ-/- and WT mice. Nevertheless, Socs1-/-IFN-γ-/- mice had pulmonary viral burdens on day 4 post-infection that were similar to IFN-γ-/- and WT controls, suggesting little effect of SOCS1 on direct innate control of viral replication in epithelial cells. Instead, SOCS1 deficiency was associated with increased humoral and cellular antiviral immunity, suggesting a regulatory effect of SOCS1 on adaptive immune-mediated viral clearance. RAG-/- mice were reconstituted with T and B cells isolated from naïve Socs1-/- IFN-γ-/- to establish animals with a SOCS1 deficiency only in adaptive immune cells. Despite increased levels of airway CD8+ T cells, RAG-/- mice reconstituted with T and B cells from Socs1-/- IFN-γ-/- mice exhibited similar levels of viral titers, airway DCs, CD4+ T cells, and antibody production compared to RAG-/- mice that received T and B cells from IFN-γ-/- mice. We are now examining whether extended type I IFN activity in Socs1-deficient mice results in improved induction of influenza-specific adaptive immunity, which then translates to increased resistance to influenza infection.
Characterization of regulatory and conventional T cell phenotype and function in HIV exposed seronegative subjects. (170.29)
Authors: Pattacini Laura , Lund Jennifer 
Published: January 2023

Abstract
The role of regulatory T cells (Tregs) in preventing or facilitating HIV infection remains unclear. To address this question, we analyzed samples from 129 HIV-exposed seronegative (HESN) individuals, divided into high and low exposure groups based on partner viral load. The two groups had comparable frequencies of Tregs, but in the higher exposure group there was a trend for increased expression of the Treg suppressive markers CD39 and CTLA4. CD4+ and CD8+ T cell activation was similar in the two groups. To assess T cell function, we measured the proliferation of T cells in response to four HIV peptide pools by a CFSE-based assay. Both low and high exposure groups showed a comparable percentage of CD4+ (12.7 % versus 9.7% respectively) and CD8+T cell proliferation (3.2% versus 4.9%). To assess the Treg suppressive function, we compared the proliferation of peripheral blood mononuclear cells (PBMCs) and Treg-depleted PBMCs in response to the peptide pools. In 41% of the samples that showed proliferation in response to at least one peptide, T reg depletion induced an increased proliferation of CD4+ T cells. The suppression was similar in high and low exposure groups. In the remaining samples, Treg depletion led to a decrease in CD4+ T cell proliferation. In conclusion, our study suggests that HESN can mount an HIV-specific T cell response and further, Treg can either suppress or assist this response, though the mechanism for this difference remains under investigation.
Absence of PI3K p110d isoform reduces viral load and morbidity of mice infected with Influenza virus (170.3)
Authors: Boesteanu Alina , Gracias Donald , Turner Martin , Katsikis Peter 
Published: January 2023

Abstract
Experimental infection of C57Bl/6 mice with influenza virus is accompanied by significant morbidity. In contrast to C57BL/6 mice, we have found that mice that lack the phosphoinositide kinase 3 (PIK3) catalytic isoform p110 delta (p110dKO) manifest significantly reduced morbidity and mortality after influenza virus infection. Throughout the infection inflammation was reduced in p110dKO mice compared to C57Bl/6 mice as determined by the total numbers of lymphocytes, B cells, T cells, macrophages and granulocytes infiltrating the lungs. Additionally lung pro-inflammatory cytokine mRNA (TNFa, MIP-2, MCP-1, IFNg) was also reduced in p110dKO mice. This was accompanied by reduced lung viral loads in p110dKO mice. We examined whether the lack of p110d in lung epithelial cells affects influenza virus replication by performing bone-marrow chimeras between p110dKO and C57Bl/6 mice. Finally, treatment of mice with a specific pharmacological inhibitor of p110d reduced significantly the mortality of mice challenged with a lethal dose of Influenza virus. These studies suggest that PI3K p110d may be a target for therapeutic intervention against influenza virus infection.
The emergence of specialized immunoregulatory antigen presenting cells in persistent infection (170.8)
Authors: Wilson Elizabeth , Brooks David 
Published: January 2023

Abstract
Persistent viral infections initially elicit robust immune responses, however multiple suppressive mechanisms are also triggered that rapidly disarm antiviral T cell responses and allow for long-term persistence. The degree of T cell suppression is determined by the integration of a concert of stimulatory and inhibitory signals. However, the mechanisms by which virus-specific T cells encounter and integrate immunomodulatory signals during viral infection are unclear. IL-10 is a key factor in suppression of anti-viral T cell responses in persistent infections. We demonstrate the emergence of a unique population of IL-10 expressing immunoregulatory antigen presenting cells (iAPC) in viral persistence. iAPC are metabolically distinct and express T cell interacting molecules in combination with high levels of multiple negative regulatory factors. This clustering of inhibitory molecules on a single APC allows for potent signals to be simultaneously delivered to T cells tipping their threshold from activation to exhaustion. We have also identified a novel mechanism, induced by infection and maintained in persistence, that leads to sustained upregulation of multiple immunoregulatory molecules, thereby serving as a rheostat to gauge levels of virus replication and translate this information to immunosuppression. Ultimately, blockade of these regulating factors in combination with targeting of iAPC populations may enhance antiviral immunity to in persistent infection.
Rapid recirculation of migrating lymphocytes between blood, lung, and liver (173.26)
Authors: Ganusov Vitaly , Auerbach Jeremy 
Published: January 2023

Abstract
Migration patterns of naive, effector, and memory lymphocytes have important implications for activation of primary and secondary immune responses and for efficient control of pathogens in peripheral tissues. Yet, quantitative details of how long it takes for lymphocytes to migrate from one tissue to another has been largely unknown. Using experimental data and mathematical modeling we estimate the rates of migration of thoracic duct lymphocytes (TDLs) from blood to multiple lymphoid and nonlymphoid tissues of a rat and back to the blood. Our model suggests extremely rapid recirculation of TDLs between blood, lung, and liver with an average residence time of cells in these tissues being less than 1 minute. The model also predicts longer residence times of TDLs in the spleen (2 hours) and major lymph nodes and Peyer's patches (8-10 hours). The same model provides a good match of independently measured output of TDLs via thoracic duct in cannulated animals. By comparing TDL accumulation in resting and antigen-stimulated lymph nodes we predict that enlargement of lymph nodes occurs because of increase entrance of lymphocytes into the inflamed LN and not decreased output as often viewed. Thus, we illustrate how within one modeling framework we can accurately describe multiple phenomena on lymphocyte recirculation in the whole organism.
Leukocyte recruitment induced by exogenous methylglyoxal: the role of endothelial adhesion molecules (173.27)
Authors: Su Yang , Lei Xi , Wu Lingyun , Liu Lixin 
Published: January 2023

Abstract
Methylglyoxal (MG) is a reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. In condition of hyperglycemia, excessive MG produced endogenously can lead to diabetic macro- and micro-vascular complications where inflammation plays an important part. However, the role of MG in the induction of inflammation and the underlying mechanisms are poorly understood. In this study, we applied MG to local, healthy tissue and used intravital microscopy to investigate the role of endothelial adhesion molecules in MG-induced leukocyte recruitment in mice. Acute administration of MG to the tissue dose-dependently induced leukocyte recruitment with ~90% recruited cells being neutrophils. The MG treatment upregulated the expression of endothelial adhesion molecules P-selectin, E-selectin, ICAM-1, but not VCAM-1. The role of these upregulated endothelial adhesion molecules in MG-induced leukocyte recruitment was confirmed by applying specific functional blocking antibodies to acute MG-treated live animals. Our data demonstrate that exogenous MG induces leukocyte recruitment through the upregulation of the expression of P-selectin, E-selectin, ICAM-1 but not VCAM-1. Our results provided mechanistic insights into the role of MG in the induction of inflammation response in conditions related to diabetic complications and revealed the role of endothelial adhesion molecules in this process.
Distinctive roles of neutrophil LSP1 and endothelial cell LSP1 during neutrophil recruitment (173.29)
Authors: Xu Najia 
Published: January 2023

Abstract
Leukocyte-specific protein 1 (LSP1) is an intracellular, F-actin- and Ca2+-binding, phosphoprotein expressed in leukocytes and endothelial cells (ECs). Using intravital microscopy and time-lapse video photography, we studied the role of neutrophil LSP1 (N-LSP1) and endothelial cell LSP1 (EC-LSP1) during neutrophil recruitment in the post-capillary venules in mice. The wild-type control, LSP1-deficient (Lsp1−/−) and their chimeric mice were used in this study. Neutrophil recruitment was induced by addition of chemokine MIP-2-containing gel to the observed cremasteric venule. Neutrophil intraluminal crawling, transendothelial migration, and chemotaxis in tissue were determined. We found that both N-LSP1 and EC-LSP1 were involved in neutrophil intraluminal crawling and neutrophil transendothelial migration. After neutrophil transmigration, only N-LSP1 was found to be important for neutrophil migration in the tissue, whereas EC-LSP1, but not N-LSP1, was essential for the directional neutrophil chemotaxis. Although N-LSP1 did not play an important role in neutrophil directional chemotaxis, both neutrophil migration and directional chemotaxis were dependent on the function of p38 mitogen-activated protein kinase, an upstream signaling molecule for N-LSP1, in the emigrated neutrophils in the tissue. Our results suggest that N-LSP1 and EC-LSP1 are both important for neutrophil recruitment but play distinctive roles in different steps of neutrophil recruitment in vivo.
Leukocyte Ig-like Receptor B4 (LILRB4) Downregulates Key Steps in the Migration of Antigen-bearing Lung Dendritic Cells to Lymph Nodes in Th2 Inflammation (173.30)
Authors: Fanning Laura , Buckley Carolyn , Xing Wei , Breslow Rebecca , Katz Howard 
Published: January 2023

Abstract
We previously reported that Lilrb4-/- mice have exacerbated Th2 immune responses and pulmonary inflammation compared with Lilrb4+/+ animals when sensitized with OVA and low-dose LPS followed by challenge with OVA. In addition, LILRB4 is selectively upregulated on Ag-bearing dendritic cells (DCs) in the lung and draining lymph nodes (LNs). Ag-challenged Lilrb4-/- mice exhibit increased migration of Ag-bearing DCs to LNs and accumulation of IL-4- and IL-5-producing LN lymphocytes. To determine how the absence of LILRB4 leads to more DCs in the LNs of Ag-challenged mice, animals were sensitized intranasally with PBS alone or OVA/LPS and were challenged with OVA. Four hours later, lungs were evaluated by immunohistology, and lung mononuclear cells were isolated for flow cytometry. The lung lymphatic vessels of Lilrb4-/- mice expressed significantly more CCL21, a chemokine that directs the migration of DCs to draining LNs. In addition, lung DCs of Lilrb4-/- mice expressed more CCR7, the CCL21 receptor. The lungs of Lilrb4-/- mice also contained significantly greater numbers of CD4+ cells expressing IL-4 or IL-5, consistent with the greater number of Ag-bearing DCs and Th2 cells in LNs and the attendant exacerbated Th2 lung pathology. Our data reveal that LILRB4 downregulates expression of two fundamental molecules that induce the migration of Ag-bearing DCs to LNs, thereby decreasing Th2 cell accumulation in LNs and lung and the ensuing pathologic pulmonary inflammation.
Intravital two-photon microscopy of immune cells in visceral adipose tissue (173.38)
Authors: Stutte Susanne , Lynch Lydia , von Andrian Ulrich 
Published: January 2023

Abstract
Obesity causes systemic low-grade inflammation predisposing to metabolic disorders including insulin resistance, diabetes, dyslipidemia and hepatosteatosis and vascular diseases. The unique repertoire of the immune population, in particular T cells and high number of macrophages within the white adipose tissue is an intriguing phenomenon. Previously, it has been shown that both cell types are implicated in adipose-derived inflammation and insulin resistance. We analyzed their cell-cell interactions, and their interactions with adipocytes to see if they result in an increased expression of leukocyte adhesion molecules, chemokines, and cytokines in adipose tissue, thereby enhancing the inflammatory response and affecting insulin signaling. For this purpose, we established the intravital two-photon microscopy on adipose tissue. Furthermore, we compare macrophages and different T cell subtypes in lean and obese mice and describe their localization and proximity to different sized adipocytes, and their migratory behavior within the tissue.