bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential contribution of IL-18 receptor beta to protective immunity and immunopathology during infection with intracellular bacteria (134.18)
Authors: Ismail Nahed , Trochtenberg Alyssa , Ghose Purnima , Jones Abrill 
Published: January 2023

Abstract
IL-18 has been shown to play a critical role in cytokine-induced organ failure during endotoxic shock. Human monocytotropic ehrlichiosis (HME) is a tick-borne infectious disease caused by E. chaffeenesis. HME is modeled in B6 mice using Ehrlichia muris (EM) that cause mild disease, and Ixodes ovatus Ehrlichia (IOE) that cause fatal shock-like syndrome. As Ehrlichia-induced septic shock and tissue injury is associated with increased IL-18 production, we examined the effect of blocking IL-18 signaling via IL-18Rβ on host defense & immune responses following sublethal (EM) and lethal (IOE) infection. Compared to IOE-infected isotype controls, in vivo IL-18Rβ neutralization in IOE-infected mice decreased bacterial burden, increased frequency of IFN-γ producing NK and NKT cells and enhanced production of TNF-α by T and non T cells on day 2 post-infection. On day 7 post-infection, blocking IL-18Rβ in lethally infected mice did not significantly influence the acquired pathogenic immune responses compared to lethally-infected isotype controls. Interestingly, blocking IL-18Rβ in the EM-infected mice increased bacterial burden, which was associated with suppressed early production of TNF-α and IFN-γ by different cell subsets compared to EM-infected isotype controls. These data suggest that IL-18Rβ may play dual protective and pathogenic roles in sublethal and lethal ehrlichial infection, respectively, through regulation of IFN-γ and TNF-α production by different innate cell subsets.
Distinct roles for IL-13 and IL-17 in chronic inflammation and fibrosis (134.8)
Authors: Wynn Thomas , Ramalingam Thirumalai , Madala Satish , Thompson Robert , Mentink Margaret , Barron Luke , Cheever Allen , Wilson Mark 
Published: January 2023

Abstract
TH2 cytokines regulate inflammation, mucus production, tissue remodeling, and fibrosis. Consequently, they have become important therapeutic targets for a number of debilitating illnesses, including asthma, idiopathic pulmonary fibrosis, ulcerative colitis, liver fibrosis, and other diseases in which TH2 cytokines are over-produced. In schistosomiasis, numerous studies have shown that TH2 cytokines play a critical role in the pathogenesis of the disease. Thus, understanding how the TH2 cytokine response is regulated during infection as well as the mechanism of action of each TH2 cytokine (IL-4, IL-5, IL-9, IL-10, IL-13, IL-21, IL-25) has been a major goal of our group over the past several years. Interestingly, in contrast to schistosomiasis-induced lung and liver fibrosis, bleomycin induced pulmonary fibrosis is associated with the development of an IL-17A-producing CD4+ and γδ+ T cell response. Studies conducted with C57BL/6 il17a-/- mice confirmed an essential role for IL-17A in bleomycin-induced fibrosis. Bleomycin-induced IL-17A production was also TGFβ dependent and recombinant IL- 17A-mediated fibrosis required TGFβ, suggesting cooperative roles for IL-17A and TGFβ in the development of fibrosis. We also found that fibrosis induced by IL-1β, which mimics bleomycin-induced fibrosis, is highly dependent on IL-17A. Together, these results suggest distinct non-overlapping immunological roles for IL-13 and IL-17A in the pathogenesis of fibrosis.
Eosinophils are required for the development of myosin-induced myocarditis and dilated cardiomyopathy (135.28)
Authors: Baldeviano Geral , Barin Jobert , Srinivasan Sachin , Chen Ping , Talor Monica , Zheng Donfeng , Bejda Djahida , Gabrielson Kathleen , Rose Noel , Cihakova Daniel 
Published: January 2023

Abstract
Eosinophilic infiltration has been associated with severe myocarditis and depressed cardiac function; however, demonstrating a causal relationship between eosinophils and myocarditis and dilated cardiomyopathy (DCM) has long remained elusive. We show here that Interleukin-5 (IL-5) is dispensable for the recruitment of eosinophils into the inflamed heart, the development of myosin-induced myocarditis (EAM) and the progression of EAM to DCM. However, IL-5-overexpressing transgenic mice developed peripheral eosinophilia, severe eosinophilic myocarditis, increased myocardial fibrosis and accelerated progression to DCM. In addition, eosinophil-deficient (dblGATA1) mice developed attenuated EAM, decreased myocardial fibrosis and greatly improved left ventricular function. Treatment with resorcinol, a specific inhibitor of eosinophilic peroxidase, significantly decreased myocarditis and myosin-induced heart hypertrophy. We conclude that eosinophils are required for the development of EAM, and the progression to DCM, at least in part through their secretion of eosinophilic peroxidase.
Abrogation of integrin α9β1-mediated signaling skews the generation of functional Th17 cells in regional lymph nodes of arthritic mice (135.3)
Authors: Kanayama Masashi , Morimoto Junko , Uede Toshimitsu 
Published: January 2023

Abstract
Th17 cells are essential regulator of autoimmune diseases. It is known that antigen presenting cells including conventional dendritic cells (cDCs) play a critical role in the differentiation of Th17 cells as the supplier of several Th17-polarizing cytokines such as IL-6 and IL-23. We have previously shown that the interaction between α9 integrin (α9) and its ligands such as tenascin-C (TN-C) enhance the production of a variety of cytokines including IL-6 by fibroblasts and macrophages. To examine the in vivo significance of α9 in Th17 development, we used murine collagen-induced arthritis (CIA). We demonstrated that α9 and TN-C were expressed by cDCs in the regional lymph nodes and the interaction between α9 and TN-C promoted the production of IL-6 from cDCs. The administration of anti-α9 antibody (55A2C) before and 2 days after first immunization with typeII collagen significantly suppressed the gene expression of IL-6 and IL-23 and the generation of Th17, but not Th1 cells in regional lymph nodes at day 7. Surprisingly at day 24, Th17, but not Th1 cell was significantly accumulated in regional lymph nodes of 55A2C-treated mice due to the down-regulation of CCR6 on Th17 cells. Nevertheless, arthritis was significantly attenuated in 55A2C-treated mice. These data suggest that α9-mediated signaling contributes to the generation of functional Th17 cells through the activation of cDCs in regional lymph node.
NODckitW/Wv mast cell deficient mice fail to develop type 1 diabetes (135.39)
Authors: Hatfield Julianne , Quirion Mary , Rao Kavitha , Brown Melissa 
Published: January 2023

Abstract
Mast cells (MCs) are innate immune cells typically known for their role in allergic responses and their ability to facilitate early immune responses to pathogens. Yet they also play a role in modifying many adaptive immune responses, including those that mediate autoimmune disorders such as EAE, the murine model of the human demyelinating disease, multiple sclerosis. We have transferred the c-kitW/Wv mutations, two independent mutations that affect MC development, onto the NOD mouse, a strain that exhibits a high incidence of spontaneous diabetes in females. NODc-kitW/Wv mice are mast cell deficient in all tissues examined, have similar mild hematopoietic deficits (macrocytic anemia) to those of the WBB6 parent strain and have normal thymic T cell compartments. In addition, they have inherited all of the 15 Idd loci tested. We demonstrate that NODc-kitW/Wv mice exhibit significantly reduced insulitis compared to wild type NOD mice and fail to develop hyperglycemia. These features correlate with the higher activation state and differential activation induced expression of inflammatory mediators in NOD mice compared to mast cells derived from the congenic diabetes resistant NOR strain of mice. Our data suggest that, as in EAE, mast cells are critical determinants of diabetes development.
Antiphospholipid (aPL) antibodies promote the release of plasma membrane-derived vesicles which inhibit the phagocytosis of apoptotic cells - role in Systemic Lupus Erythematosus (SLE) (135.9)
Authors: Antwi-Baffour Samuel , Kholia Sharad , Inal Jameel 
Published: January 2023

Abstract
Plasma Membrane-derived Vesicles (PMVs) are membrane-coated vesicles of diameter 0.1 to 1 µm, carrying various proteins inherent in their parental cells. PMVs are released when cells undergo activation/apoptosis via blebbing and shedding. Exposition of phosphotidylserine (PS) on the outer membrane leaflet could explain a role for PMVs in phagocytosis and thrombosis. Increased PMV release, although controlled, is a sign of cellular dysfunction and indicator of cell injury or stress. Patients with inflammatory disease such as Systemic Lupus Erythematosus (SLE) show increased PMV levels in plasma, accompanied by persistent apoptosis and defective clearance which correlates with disease activity. Although still unclear, impaired clearance of apoptotic cells (ACs) may represent a mechanism for the development or enhancement of SLE. Both PMVs and ACs express PS on the outer leaflet of the lipid bilayer as a marker for phagocytosis. We found that PMVs dose dependently inhibit the phagocytosis of ACs by competing for the PS receptor on macrophages. Phosphotidylserine is directly involved as annexin V-labelled PMVs reversed the PMV-mediated inhibition of phagocytosis. We further confirmed elevated PMV levels in SLE patient plasma and showed that the aPL antibodies from the plasma of such patients induced the release of PMVs. These findings show that PMVs can modulate phagocytosis of ACs and suggest an alternative mechanism for PMV enhancement of inflammatory responses.
Modulation of the RIG-I/MDA5-MAVS-dependent signaling pathway by distinct LCMV components shapes type I interferon responses (136.12)
Authors: Zhou Shenghua , Cerny Anna , Fitzgerald Katherine , Welsh Raymond , Kurt-Jones Evelyn , Finberg Robert 
Published: January 2023

Abstract
Early and efficient induction of type I IFN and other interferon-stimulated genes following virus infection is essential for the control of the viral infection, and this induction is mostly controlled by the innate immune system via pattern-recognition receptors (PRRs), including the endosomal Toll-like receptors and the retinoic acid inducible gene-I like RNA helicases RIG-I and MDA5. The prototypic arenavirus, Lymphocytic choriomeningitis virus (LCMV), is an excellent system to study the impact of virus-host interactions on viral pathogenesis. Although most aspects of LCMV model have been extensively studied and the findings obtained from this model have been used to interpret the pathogenesis of human viral diseases, the molecular mechanisms by which LCMV modulates type I IFN responses are not clear. Better understanding of these mechanisms is critical for the development of novel vaccines and effective antiviral therapeutic strategies against arenavirus infection. In the present study, we demonstrate that LCMV genomic RNA activates the RIG-I/MDA5-MAVS-dependent signaling pathway to induce type I IFN responses. We further demonstrate that LCMV nucleoprotein inhibits LCMV RNA induced type I IFN responses by physically interacting with both RIG-I and MDA5 signaling molecules. These results indicate that interactions between LCMV viral proteins and viral genomic RNA and the host signaling molecules are critical to regulate the virus induced innate immune response.
Expression patterns of Human Interferon-alpha and Interferon-lambda subtypes by monocytes, dendritic cells and B cells. (136.14)
Authors: Schramm Lynnsie , Mane Viraj , Bykadi Srikant , Navarro Maria , Jubin Ronald , Rabin Ronald 
Published: January 2023

Abstract
Human interferon-alpha comprises a family of thirteen highly homologous genes and twelve subtypes (coding sequences of IFN-alpha1 and -13 are identical). We employed two modifications of fluorescent-labeled probe technology--molecular beacons (MB) and locked-nucleic acids (LNA) to develop a highly efficient, sensitive, and specific quantitative RT-PCR assay for each human IFN-alpha subtype as well as the three subtypes of IFN-lambda, and for completion, IFN-beta and -gamma. The assay is formatted to a 384-well plate that measures 16 samples/plate and includes four-point standards for each IFN. Using this assay, we determined expression patterns of these IFN by monocytes, monocyte-derived macrophages and dendritic cells (MDM and MDDC), primary mDC, pDC and B cells in response to ligands for TLR 3, 4, and 9. All the myeloid cells, including mDC expressed high levels of IFN-beta and -lambda1, and moderate levels of IFN-alpha. pDC expressed high levels of almost all IFN, although with quantitative and in one case, a qualitative difference in between the response to CpG (TLR9) vs. imiquod (TLR7). B cells also expressed IFN—more subtypes than myeloid cells, but and fewer than pDC. Type I IFN expression was always accompanied by type III IFN expression. We conclude that IFN expression patterns are both ligand and cell-type specific. Subtypes alone or in combination may have unique roles in the innate immune response.
Identification of glycolipid ligands for human MINCLE. (136.22)
Authors: O'Callaghan Chris , Anita Mistry , Dunbar Rod , Feizi Ten , Liu Yan , de Sa Palma Maria , Fenton-May Angharad 
Published: January 2023

Abstract
We are studying the role of C-type lectin-like molecules in innate immunity. We have produced recombinant human MINCLE (CLEC4E) protein and generated a specific antibody against this. We find limited expression in a range of immune cells. Human MINCLE co-immunoprecipitates with the FcR gamma chain. Recombinant MINCLE was screened for binding to a variety of glycan arrays and found to bind to several glycolipids, including synthetic glycolipids. Using a quantitative cellular reporter assay, these glycolipids were shown to cause potent cellular activation through MINCLE. Further investigation are underway to assess the relevance of the interactions of MINCLE in human disease. These ligands have great potential as adjuvants.
NLRP3 inflammasome participates in lysosomal destabilization in macrophages exposed to the bacterial toxin tetanolysin O (136.30)
Authors: Heid Michelle , Chu Jessica , Sun Chengqun , Thomas L. , Nuñez Gabriel , Watkins Simon , Salter Russell 
Published: January 2023

Abstract
The NLRP3 inflammasome is a multiprotein complex that includes the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which binds with capase-1 via CARD-CARD interactions and is involved with capase-1 activation. Our lab has previously shown that exposure of murine bone marrow derived macrophages (BMDM) with the cholesterol dependent cytolysin tetanolysin O (TLO), produced by Clostridium tetani, activates the NLRP3 inflammasome and induces IL-1beta secretion. Furthermore, we have shown that TLO treatment of BMDM results in the loss of acidity in lysosomes. In this study, our objective was to determine if the effects of TLO on the lysosome in BMDM are dependent upon NLRP3 and whether the inflammasome plays a role in lysosomal destabilization. Our data show that in NLRP3-deficient macrophages lysosomal permeabilization is diminished following toxin exposure relative to equivalently treated wild type cells. The results to be presented further our understanding of how NLRP3 functions in macrophages exposed to stressful stimuli such as bacterial toxins.
Size and shape matter: Role of surface curvature in inflammasome activation by synthetic microparticles (136.39)
Authors: St. Pierre Christine , Zhu Jinato , Hayward Ryan , Kurt-Jones Evelyn 
Published: January 2023

Abstract
The human immune system is poised to recognize and respond to foreign particulate substances, like crystals, pollen, bacteria or fungal spores. While some particles can induce significant inflammation others are relatively non-inflammatory. The physical and chemical characteristics that determine the response to different particles are unclear. In this study, we sought to systematically examine the roles that particle size, shape, and surface texturing play in uptake efficiency and subsequent immune cell activation. Using a novel micro-capillary flow focusing technique, we generated microparticles of similar composition but varying in shape from spherical to budding. We discovered that particles with high surface curvature (budding particles) were associated with and phagocytosed by macrophages at higher frequency than particles with low surface curvature, i.e., smooth particles. Remarkably, budding particles also induced stronger IL-1β secretion than smooth particles, through activation of the Nalp3 inflammasome-signaling complex. In vivo, budding particles induced more rapid neutrophil recruitment to the injection site, a hallmark of acute inflammation, than spherical particles. Although currently underappreciated, these findings demonstrate a remarkable and pronounced role for particle shape and surface curvature, independent of chemical composition and surface ligand recognition, in immune cell activation.
TLR3 Reduces Hepatitis C Viral Replication in Human Hepatocytes (136.7)
Authors: Eksioglu Erika , Bayouth Lily , Bess Jennifer , Zhu Haizhen , Liu Hongyan , Darwiche Houda , Nelson David , Liu Chen 
Published: January 2023

Abstract
Background: During an acute viral infection the intracellular innate immune defense is activated through the production of type I IFN and not well understood. We have developed an experimental model showing that HCV can induce IFN in LH86 cells, which have wild type TLR3 and RIG-I expression. The aim of this study is to examine how HCV induces IFN and the role of TLR in acute infection. Methods: LH86 and Huh7.5 cells and their transfected counter parts (LH86 siRIG-I, siTLR3 and siTLR7and Huh7.5 RIG-I, TLR3 and TLR7) were tested in an infectious JFH-1 HCV cell culture system. The IFN induction and antiviral efficacy of RIG-I in HCV infection was determined using real-time PCR. We also measured apoptosis by light microscopy and by flow cytometric analysis of Annexin-V expression. Results: Our data show that TLR3 is important for the induction of IFNβ in LH86 cells since silencing it prevents its production as well as the cytopathic effects normally observed in this cell line. Forced stable expression of wild type TLR3 and TLR7 in Huh7.5 cells partially restored the induction of IFN and significantly reduced the replication of the virus in an 80 day culture, with TLR3 having the greatest impact. The induction of IFN is strongly correlated with this antiviral effect. At the same time the virus decreases the expression of TLRs. Conclusion: Our study indicates that TLR3 and RIG-I in liver cells play a key role in anti-HCV defense.
Intravital 2P-imaging reveals anti-viral CTL mediate fatal pathology by recruiting myelomonocytic cells (137.17)
Authors: McGavern Dorian , Kang Silvia , Kim Jiyun , Dustin Michael 
Published: January 2023

Abstract
Many viruses can cause severe neurological complications in the central nervous system (CNS) through initiation of immunopathology. A case in point is the fatal meningitis induced by lymphocytic choriomeningitis virus (LCMV) - a disease associated with vascular breakdown and seizures. Although LCMV-specific CNS-infiltrating cytotoxic lymphocytes (CTL) are essential for disease, it is not known precisely how CTL mediate fatal immunopathology. Recently, it has become possible to directly observe immunity and immunopathology using two photon laser scanning microscopy (TPLSM). We initiated our real time studies of LCMV-induced meningitis by visualizing LCMV-specific CTL dynamics in the meninges during the onset of symptoms. Our findings yielded a novel and unexpected mode of pathogenesis defined by CTL trafficking into the meningeal space followed by a massive secondary recruitment of pathogenic myelomonocytic cells (i.e., monocytes and neutrophils). Importantly, myelomonocytic cells were responsible for severe vascular leakage and rapid onset disease during meningitis, and CTL directly participated in their recruitment by releasing myelomonocytic cell chemoattractants. Our results demonstrate that a CD8+ T cell dependent disorder can proceed in the absence of CTL effector mechanisms and rely instead on secondarily recruited myelomonocytic cells.
CD11c high dendritic cells regulate the reestablishment of vascular quiescence and stabilization after lymph node vascular expansion (138.10)
Authors: Tzeng Te-Chen , Chyou Susan , Tian Sha , Webster Brian , Carpenter April C. , Lu Theresa T. 
Published: January 2023

Abstract
Lymph node expansion during immune responses is accompanied by rapid vascular expansion. The maturation of the newly expanded vasculature and the regulatory mechanisms involved have not been well studied. We show that while initiation of vascular expansion in immune-stimulated nodes is associated with upregulated endothelial cell proliferation, increased high endothelial venule trafficking efficiency and VCAM-1 expression, and disrupted perivascular fibroblastic reticular cell organization, the reestablishment of vascular quiescence and stabilization after expansion is characterized by reversal of these phenomena. While CD11c medium cells are associated with the initiation of vascular expansion, CD11c hi MHCII med dendritic cells accumulate later and their short-term depletion in mice abrogates the reestablishment of vascular quiescence and stabilization. CD11c hi MHCII med cells promote endothelial cell quiescence in vitro and, in vivo, mediate quiescence at least in part by mediating reduced lymph node VEGF. Disrupted vascular quiescence and stabilization in expanded nodes is associated with attenuated T cell-dependent B cell responses. These results describe a novel mechanism whereby CD11c hi MHCII med dendritic cells regulate the reestablishment of vascular quiescence and stabilization after lymph node vascular expansion and suggest that these dendritic cells function in part to orchestrate the microenvironmental alterations required for successful immunity.
Neural control of acetylcholine release by T cells attenuates TNF production in endotoxemia (138.24)
Authors: Rosas-Ballina Mauricio , Ochani Mahendar , Olofsson Peder , Valdés-Ferrer Sergio , Chavan Sangeeta , Tracey Kevin 
Published: January 2023

Abstract
The cholinergic anti-inflammatory pathway regulates pro-inflammatory cytokine production through vagus nerve signaling via the α7 subunit of the nicotinic acetylcholine receptor expressed on macrophages. Vagus nerve stimulation requires an intact splenic nerve to attenuate TNF production by spleen macrophages. Despite exhaustive search, cholinergic fibers have not been observed in spleen. Here, we used transgenic mice that express enhanced green fluorescent protein (eGFP) under control of transcriptional regulatory elements of choline acetyltransferase, the enzyme that synthesizes acetylcholine. eGFP was detected in spleen B and T cells, some of which were located in close proximity to catecholaminergic nerve endings in the parenchyma of the white pulp. Vagus nerve stimulation significantly increased acetylcholine levels in spleen. In vitro, adrenergic stimulation induced the release of acetylcholine by spleen lymphocytes through a β2 adrenergic receptor dependent mechanism. Vagus nerve stimulation failed to suppress TNF in endotoxemic nude mice, and transfer of CD3+ T cells into nude mice restored vagus nerve control of cytokine production. Together, these data identify T cells as an essential component of the cholinergic anti-inflammatory pathway, and suggest that neural signals increase acetylcholine release from spleen T cells, which in turn attenuates TNF production in spleen via α7 expressed on innate immune cells.