bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic infection with Toxoplasma gondii potentiates the immune response against polymicrobial infection in an IFN-gamma and TNF - mediated pathway, which can be harmful to the host (164.18)
Authors: Souza Maria , Fonseca Denise , Kanashiro Alexandre , Bonfá Giuliano , Benevides Luciana , Alves-Filho José Carlos , Cunha Fernando , Silva João 
Published: January 2023

Abstract
Introduction: The majority of studies regarding host-pathogen interactions have focused on a single pathogen. However, host organisms in a natural environment are commonly exposed to multiple pathogens, such as T. gondii infection, which induces a strong immune response by Th1 pathway, that can persists throughout the life of the host. Therefore, we hypothesized that chronic infection with T. gondii could alter the course of host response against bacterial infection. Methodology: C57BL/6 mice were orally infected with 5 cysts of ME-49 strain of T. gondii and 40 days post infection, subjected infection by cecal ligation and puncture (CLP) sepsis model. Results: Our data showed that, 12 and 24 hours after of CLP, the group of mice infected with T. gondii exhibited decreased bacterial count, increased inflammation characterized by an increase in myeloperoxidase content in lung and increase in IFN-γ and TNF cytokines levels, as compared mice subjected to the same stimulus infectious without previous T. gondii infection. Moreover, after CLP, these animals showed a significantly increase in mortality rate, which was reduced in mice TLR-2 knockout or treated with low concentrations of anti-IFN-γ or anti-TNF antibodies. Conclusion: This study demonstrates that T. gondii infection potentiates the host response against polymicrobial infection, which can be harmful to the host. The mechanism by which this happens seems to be mediated via the overproduction of IFN-γ and TNF.
Identification and characterization of the recently evolved littoral cell as the chief source of SIRPα in human spleen (169.1)
Authors: Ogembo Javier , Milner Dan , Fingeroth Joyce 
Published: January 2023

Abstract
Asplenic individuals are compromised not only in their ability to destroy infectious agents, but are at increased risk of death from autoimmune disease, certain tumors, and ischemic heart disease. Enhanced mortality is attributed to lack of phagocytes sequestered in spleen that efficiently engulf and destroy appropriate targets, though related cells are found elsewhere in man. To investigate whether a unique population(s) regulates RBC and pathogen clearance and possibly filtration of altered self, we focused on a little-characterized cell that dominates the splenic red pulp of man and closely related primates, the venous sinus lining or littoral cell (LC). High expression of the formin FHOD1 outlines the LC population. Though endothelial-like in distribution LCs express several macrophage-associated proteins, the RBC antigen DARC and T-cell co-receptor CD8α/β though they lack lineage markers CD34 and CD45. Strikingly, SIRPα (CD172a) expression in human spleen concentrates on the LC, consistent with a key role in RBC turnover and elimination versus release of infected or altered self. Human LCs (SIRPα+, FHOD1+, CD8α+, CD34-, CD45-) comprise a highly specialized barrier cell population that emerged late in the course of evolution upon CD8 expression. Unique to higher primates (Hominidae), LCs may provide the ultimate filtration function(s) of human spleen.
Systemic administration of metallic nanoparticles initiates an acute, NALP3-mediated, inflammatory response (169.8)
Authors: Fernandez-Cabezudo Maria , Sarawathiamma Dhanya , Nemmar Abderrahim , Haik Yousef , Al-Ramadi Basel 
Published: January 2023

Abstract
Nanoparticles are increasingly being commercialized for use in biomedicine. Given their inorganic metal makeup, nanoparticles have been thought to be biologically inert. However, there is accumulating evidence demonstrating that, due to their exceedingly small size, inorganic particles may have deleterious effects on pulmonary function. In this study, we investigated the potential immunotoxicity associated with systemic administration of composite inorganic nanoparticles. Using a murine model, the acute effect of intraperitoneal inoculation of metallic nanoparticles was studied by monitoring changes in hematological and inflammatory parameters as well as serum levels of organ toxicity indicators, including AST, ALT, LDH, BUN and creatinine. Our findings indicate that high dose systemic exposure is associated with acute liver injury due to preferential accumulation of nanoparticles in this organ. Moreover, injection of nanoparticles resulted in the activation of phagocytic cells and the secretion of proinflammatory cytokines. Utilizing several lines of gene-deficient animals, we demonstrate that the nanoparticle-triggered response is dependent on the NALP3 inflammasome. These findings suggest that nanoparticles may be subject to recognition by the innate immune system.
Coxsackie virus entry and spread in HeLa cells is aided by microvesicle release (170.22)
Authors: Jorfi Samireh , Ansa-Addo Ephraim , Inal Jameel 
Published: January 2023

Abstract
Microvesicles(MVs) released from plasma membrane expressing surface phosphatidylserine and ranging from 0.2-≤1 μm in diameter are reported to carry various membrane proteins, lipids and cytoplasmic components characteristic of the parental cell. Coxsackie virus B (CVB), a member of the enterovirus family is the main cause of meningitis and encephalitis in infants which may result in neurodevelopmental defects. Calpains are calcium-dependant cysteine proteases that degrade cytoplasmic and cytoskeletal proteins. They regulate a variety of actin-dependant cellular processes such as microvesiculation. CVB1 requires calpain activation for both entry and virus replication. Here, we show that knocking down calpain, using approaches such as small interfering RNA (siRNA), culminates in reduction of MV release, which then abrogates CVB1 entry and spread in HeLa cells. The calpain inhibitor calpeptin also caused similar reduction in CVB1 entry and spread to healthy target cells. Together, our findings provide evidence that CVB1 infected HeLa cells enhance MV production, and these MVs aid the spread of infection. Furthermore, inhibition of MV release using siRNA results in inhibition of CVB1 entry and spread.
Reduced OPP susceptibility in naturally exposed lambs with homozygous TMEM154 K35 genotypes. (170.30)
Authors: Chitko-McKown Carol , Leymaster Kreg , Heaton Michael , Clawson Michael , Harhay Gregory 
Published: January 2023

Abstract
Ovine progressive pneumonia virus (OPPV) is a small ruminant lentivirus of the Retroviridae family that infects sheep worldwide. Our research group recently identified a mutation (K35) within ovine gene TMEM154 that associated with reduced susceptibility to OPPV. The ancestral state for TMEM154 is E35. The mechanism responsible for reduced OPPV susceptibility is unknown. Lambs that were homozygous K35 (n = 64), homozygous E35 (n = 58), or heterozygous E35K (n = 80) and born to OPPV sero-positive ewes were produced to test the association of E35K with OPPV susceptibility. Lambs were bled one week post-weaning and every 5 weeks thereafter to determine serological status. At 7 months of age, lambs were co-mingled with a flock of sero-positive mature ewes during a 35-day breeding season to re-expose lambs to OPPV as naturally occurs during breeding in infected flocks. Mature ewes were removed after breeding and lambs were again bled at 5-week intervals. At 7 months of age, 11% of homozygous K35 lambs were sero-positive for OPPV, compared to about 25% of lambs with one or two copies of the susceptible E35 ancestral allele. Two months after re-exposure to the infected ewes, 25% of homozygous K35 lambs were sero-positive, compared to 42% of heterozygous E35K lambs and 38% of homozygous E35 lambs. This study confirms that homozygous K35 lambs are less susceptible to OPPV infection and provides the first evidence of dominance of the E35 allele relative to K35.
Interaction of PB1 domain-containing signaling molecules in the regulation of Th2 response (174.16)
Authors: Yang Jun-Qi , Liu Hongzhu , Moscat Jorge , Diaz-Meco Maria 
Published: January 2023

Abstract
Phox and Bem1 (PB1) domains are protein interaction modules which contain approximately 80 amino acids and are found in a number of cytoplasmic signaling proteins. PB1 domain-containing molecules include signaling adapters p62 and Par-6, kinases such as MEK5α, MEKK3, atypical PKCs (aPKCs) PKCζ and PKCλ/ι, as well as the newly discovered NBR1 (neighbor of BRCA1 gene 1), etc. They participate in diverse biological processes. We have recently reported that PKCλ/ι and NBR1 can regulate Th2 differentiation and function both in vivo and in vitro. Here, we demonstrated that PKCλ/ι NBR1 and p62, the three important PB1 domain-containing signaling molecules, all were recruited to immunological synapses between activated CD4+ T cells and anti-CD3/CD28-coated latex beads, or between Jurkat cells and Raj B cells loaded with SEE super antigen. These three signaling molecules were found co-localized with lipid rafts of cell membranes, which is believed important for signaling transduction. Furthermore, PKCλ/ι, NBR1 and p62 were able to directly interact each other as confirmed by immunoprecipitation and confocal staining. The three signaling molecules can regulate nuclear factor of activated T cells (NFAT) c1 activity, which is actively involved in Th2 differentiation and function. Therefore, we identify a novel mechanism by which PB1 domain-containing signaling molecules control Th2 response, at least in part through NFATc1.
B cells as master regulators of a pro-inflammatory T cell balance in obesity and glucose intolerance (176.17)
Authors: Belkina Anna , Snyder-Cappione Jennifer , Jagannathan-Bogdan Madhumita , Carr Jordan , DeFuria Jason , Markham Douglas , Allen Jessica , Bouchard Jacqueline , Nersesova Yanina , Watkins Amanda , McDonnell Marie , Apovian Caroline , Denis Gerald , Nikolajczyk Barbara 
Published: January 2023

Abstract
Lymphocytes play key roles in the chronic inflammation critical for T2D pathogenesis. T2D patients have an elevated ratio of pro- to anti-inflammatory T cells, and B cells that fail to produce anti-inflammatory IL-10. New data show that B cells from the diet-induced obesity (DIO) mouse model of T2D secrete a pro-inflammatory balance of cytokines, including relatively low IL-10 production, which mirrors our findings in T2D patients. DIO B cells do not secrete auto-antibodies, as evidenced by anti-nuclear antigen staining. Complementary metabolic studies show that B cell-null μMT mice resist the development of glucose intolerance (but not obesity) in response to DIO. Taken together, these data support the conclusion that a pro-inflammatory B cell cytokine balance, rather than antibodies, promotes T2D. To further define roles for B cells in T2D, we immunophenotyped DIO μMT splenocytes. Regulatory T cells (Tregs) expand in DIO μMT, while Tregs fail to expand in WT mice. These data are consistent with new human studies showing B cells from T2D (but not healthy) subjects support pro-inflammatory T cells, and indicate clinical relevance of published studies showing decreased Th1 function in DIO μMT vs. WT mice. We conclude B cells are critical regulators of inflammation in T2D due to 1. Secretion of a pro-inflammatory cytokine balance; and 2. An ability to promote pro-inflammatory T cell function. Thus B cell depletion may represent a valuable tool in the T2D clinic.
Mast cells activate MDSC to promote inflammation (177.2)
Authors: Morales Johanna , Faber Travis , Saunders Bryan , Graham Laura , Norton Sarah , Bear Harry , Lantz Chris , Conrad Daniel , Ryan John 
Published: January 2023

Abstract
Mast cells play an important role in promoting inflammation, controlling parasitic infection, and potentiating allergic disease. Conversely, myeloid-derived suppressor cells (MDSC) are found in tumor-bearing individuals and in models of septic shock, where they are known to have regulatory effect. We aimed to determine a possible role for interactions between MDSC and mast cells and the effect of these interactions in a mouse model of parasitic infection. Surprisingly, co-culture of these cells resulted in a drastic increase in pro-inflammatory mediator release, which was attributed entirely to MDSC. Depletion of MDSC from mice infected with Nippostrongylus brasiliensis resulted in delayed worm expulsion and a drastically increased intestinal worm burden. Conversely, this inflammatory role of MDSC seems detrimental when inflammation is chronic, as MDSC depletion in an airway hyperresponsiveness model decreased the pathology of this disease. Interestingly, we have found that mast cell conditioned-media activates both the STAT3 and ERK pathways in MDSC, which could represent a novel means of pro-inflammatory cytokine induction in MDSC. We therefore conclude that mast cells can reprogram MDSC to a pro-inflammatory phenotype, suggesting that the evolutionary purpose of these suppressive cells may be to potentiate inflammatory Th2 responses necessary for parasite expulsion.
Lantrunculin B-induced filamentous actin disassembly enables human mast cell degranulation by SCF alone (177.7)
Authors: Smrž Daniel , Beaven Michael , Metcalfe Dean , Gilfillan Alasdair 
Published: January 2023

Abstract
The release of inflammatory mediators from mast cells following antigen/IgE-mediated FcϵRI aggregation induces allergic reactions including anaphylaxis. Stem cell factor (SCF), the ligand for the mast cell growth factor receptor KIT, potentiates such release. However, despite inducing similar early signaling events as antigen, SCF alone induces minimal, if any, degranulation in the absence of other stimuli. We therefore investigated whether the process underlying these differences may lie in receptor-induced distal events involving the reorganization of the actin cytoskeleton. To explore this issue, we utilized latrunculin B, an inhibitor of actin polymerization which is known to potentiate FcϵRI-mediated mast cell degranulation. As expected, latrunculin B moderately potentiated IgE/antigen-induced human mast cell degranulation, This response was, however, markedly enhanced in the presence of SCF (100 ng/ml), especially at lower antigen concentrations, suggesting that the SCF dependent component was more sensitive to latrunculin B than the antigen component. Furthermore, although SCF alone failed to induce degranulation, in the presence of latrunculin B, it induced degranulation in a concentration-dependent manner to a similar extent as that produced by IgE/antigen. These data thus suggest that SCF provides inadequate signals for the necessary remodeling of the actin filament network for degranulation which is rectified by latrunculin B.
Regulation of the ribosomal protein S6 by CARMA1 and MALT1 (178.1)
Authors: Hamilton Kristia , Kane Lawrence 
Published: January 2023

Abstract
The ribosomal protein S6 is a downstream target of the PI3K/Akt/mTOR pathway, which promotes cellular growth and proliferation. Hyper-activation of the mTOR pathway has been implicated in cancer progression as well as resistance to therapies. Activation of S6 occurs through engagement of growth factor receptors and through the T cell receptor and co-stimulatory molecules in T cells. Here we show that activating S6 upon T cell stimulation is mediated through the proteins CARMA1 and MALT1. Using a mutant T cell line deficient in CARMA1 (JPM50.6), we observed decreased S6 phosphorylation upon TCR/CD28 stimulation compared with wild type T cells. Knockdown of CARMA1 in Jurkats (CARMAshRNA) also followed this trend. Notably, we also found decreased S6 phosphorylation in Jurkats expressing little MALT1 (MALT1shRNA) with T cell stimulation. Investigation into the mechanism of CARMA1 and MALT1 activation of S6 revealed a prominent role for the kinase p70S6K, a downstream target of mTOR. We noted impaired induction of S6K phosphorylation in JPM 50.6 and MALT1shRNA cells, compared with Jurkats, after TCR/CD28 stimulation. Additionally, use of the MALT1 caspase inhibitor, z-VRPR-fmk, was shown to inhibit TCR/CD28 mediated S6 phosphorylation in Jurkats and primary CD4+ T cells. These findings reveal a novel pathway for S6 activation in T cells through CARMA1, MALT1 and p70S6K.
Protective action of regulatory T cells in ischemic kidney injury requires adenosine 2A receptor signaling and PD-1 (178.15)
Authors: Kinsey Gilbert , Huang Liping , Khutsishvili Konstantine , Ye Hong , Lobo Peter , Okusa Mark 
Published: January 2023

Abstract
Regulatory T cells (Tregs) suppress innate inflammation and injury associated with kidney ischemia-reperfusion injury (IRI). Tregs express CD73, which is the final enzyme in production of extracellular adenosine and previous studies have demonstrated that adenosine 2A receptor (A2AR) activation on immune cells protects against IRI. We hypothesized that the production of adenosine by adoptively-transferred Tregs is required to block innate immune responses in kidney IRI and that the Treg-generated adenosine would signal through A2ARs on inflammatory cells and in an autocrine manner on Tregs. Adoptively-transferred WT Tregs protected WT mice from kidney IRI, but in the absence of adenosine generation (CD73KO Tregs) or A2ARs (A2ARKO Tregs), Treg function was completely inhibited. Pharmacologic A2AR stimulation in CD73KO Tregs, prior to adoptive transfer, restored their protective ability, and augmented the ability of WT Tregs to suppress kidney IRI. Surface expression of the negative co-stimulatory molecule PD-1 is enhanced in Tregs by A2AR signaling. PD-1 blocking antibody treatment of Tregs, prior to adoptive transfer, reversed their protective effects in vivo, even if they had been pre-treated with an A2AR agonist. Taken together these findings demonstrate that the simultaneous ability to generate and respond to adenosine is required for Tregs to suppress innate immune responses in ischemia-reperfusion injury through a PD-1-dependent mechanism.
High dose antigen stimulation leads to binding defects caused by persistent spatial segregation of TCR and CD8 in cytotoxic T cells (178.9)
Authors: Perica Karlo , Bieler Joan , Schneck Jonathan 
Published: January 2023

Abstract
The lateral organization of surface receptors controls ligand binding and activation. Our group has shown that activated T Cells exhibit persistent clustering of T Cell Receptor (TCR) several days after stimulation, leading to enhanced binding of soluble Major Histocompatibility Complex (MHC) dimers at low concentrations. In contrast, other groups have shown a complete loss of binding in activated T Cells during the same time period. Here, we resolve this contradiction by demonstrating that persistent binding behavior is controlled by the dose of antigen during primary activation. T Cells from TCR transgenic mice stimulated with high but not low dose of peptide are unable to specifically bind soluble Kb-SIY or Db-GP100 MHC dimer four days after stimulation. The behavior is not due to differences in the surface expression of TCR, CD8alpha, or CD8beta. Cytokine production mirrors the loss of binding. However, both high and low dose stimulated cells are able to bind the so-called ‘CD8 independent’ Ld-QL9 dimer, implicating the coreceptor in the binding defect. Using biophysical binding assays, k-space Image Correlation Spectroscopy, and Forster Resonance Energy Transfer between TCR and CD8, we demonstrate that TCR and CD8 are segregated, and TCR unclustered, on high dose activated T Cells, impairing CD8-dependent binding. Thus, membrane organization derived binding defects represent a mechanism for controlling T Cell responses to supraoptimal antigen.
TOLL-LIKE RECEPTOR 4 PLAYS AN ESSENTIAL ROLE IN EARLY SKIN WOUND HEALING (180.1)
Authors: Chen Lin , Guo Shujuan , Ranzer Matthew , DiPietro Luisa 
Published: January 2023

Abstract
Toll-like receptor 4 (TLR4) plays a key role in the initiation of innate immunity and in the regulation of adaptive immune responses. Using microarray analysis and PCR, TLR4 expression was observed to increase in experimental murine skin wounds at the early stages, suggesting a role in wound inflammation. Closure of excisional wounds was significantly delayed in TLR4 deficient (C3H/HeJ) as compared to wild type mice, and both IL-1β and IL-6 production were significantly lower in the wounds of TLR4 deficient mice. EGF also markedly decreased in the wound edge of epidermis in TLR4 deficient mice. In vitro studies confirmed that a wound stimulus induces TLR4 mRNA expression in primary normal human epidermal keratinocytes (NHEK). In vitro injury also induced the phosphorylation of p38 and JNK MAPK, as well as the expression of IL-1β and TNF-α by NHEK. Blockade of TLR4 abolished the phosphorylation of p38 and JNK MAPK, and blockade of TLR4 and/or p38/JNK abolished IL-1β production. The results strongly suggest that inflammatory cytokine production by injured NHEK is stimulated via the TLR4-p38 and JNK MAPK signaling pathway. Together, the current results provide evidence for a role of TLR4 at sites of injury, and suggest that TLR4 is an important regulator of wound inflammation.
The Asp299Gly polymorphism alters TLR4 signaling by interfering with recruitment of adapter proteins MyD88 and TRIF (180.5)
Authors: Medvedev Andrei , Figueroa Leandra , Xiong Yanbao , Song Chang , Piao Wenji 
Published: January 2023

Abstract
The Asp299Gly (D299G) and, to a lesser extent, Thr399Ile (T399I) TLR4 polymorphisms have been associated with Gram negative sepsis and infectious diseases, but the mechanisms by which they affect TLR4 signaling are unclear. In this study, we determined the impact of these polymorphisms on TLR4 expression, TLR4- MD2 interactions, LPS binding, and activation of MyD88- and TRIF-dependent pathways. Complementation of HEK293/CD14/MD2 transfectants with WT or mutant YFP-TLR4s revealed similar TLR4 expression levels, TLR4-MD2 interactions, and LPS binding. The presence of the D299G polymorphism led to impaired LPS-induced phosphorylation of p38 and TBK-1, activation of NF-κB and IRF-3, and induction of IL-8 and IFN-β mRNA. The T399I TLR4 species elicited responses that showed no statistical difference with those caused by WT receptor. In contrast to WT TLR4, expression of the D299G mutant in TLR4-/- mouse macrophages failed to elicit LPS-mediated induction of TNF-α and IFN-β genes. Co-immunoprecipitation revealed deficient LPS-elicited interaction of MyD88 and TRIF with D299G TLR4, in contrast to robust adapter recruitment to WT TLR4. Our data indicate the D299G polymorphism compromises TLR4 signaling by impairing recruitment of MyD88 and TRIF, suggesting that its interference with TLR4 dimerization and assembly of docking platforms in the TIR domains that enable adapter recruitment