bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIM-3 is involved in NO imbalance of Atherosclerosis through the IkappaB/NF-kappaB Pathway (91.6)
Authors: Hou Nan , Liu Ying , Ju Ying , Zhang Xiaoning , Zhao Di , Zhang Zhenyu 
Published: January 2023

Abstract
TIM-3 (T cell immunoglobulin and mucin domain-3) is proved to regulate the immune system in many inflammaroty diseases. However, the role of TIM-3 on atherosclerosis has not been studied. We found TIM-3 was highly expressed on monocytes/macrophages of human peripheral blood,but low on T cells, either CD4+ or CD8+ T cells. And the level of Tim-3 expression on monocytes/macropahges from patients with atherosclerotic disease was higher than that from healthy subjects (93.35¡À12.14% vs 81.04¡À 24.07%,t=4.968,P&lt;0.0001). Immunochemistry staining demonstrated the upregualtion of Tim-3 on RAW264.7, a macrophage like cell line, incubated with oxidized low-density lipoprotein (oxLDL) or LPS. Moreover, Tim-3 blocking antibody acted as an adjuvant during Nitic oxide (NO) production of RAW 264.7.Consistent to that,overexpresstion of Tim-3 by transfection inhibited NO production of RAW264.7.Futher study showed Tim-3 blocking antibody enhanced phosphorylation of NF-kappaB p65 and degradation of IkappaB.Thus TIM-3 inhibits NO production of macrophages mainly through the IkappaB/NF-kappaB pathway and is involved in NO imbalance in Atherosclerosis.
correspondence to: Professor Chunhong Ma, Institute of Immunology, Shandong University School of Medicine.E-mail address: machunhong@sdu.edu.cn.
Characterization of folate receptor positive macrophages and monocytes and folate receptor-mediated specific targeting in inflammation (92.10)
Authors: Xia Wei , Hilgenbrink Andrew R , Matteson Eric L , Lockwood Michael B , Morgenstern David E , Cheng Ji-Xin , Low Philip S 
Published: January 2023

Abstract
Folate receptor (FR) expressing macrophages have been shown to play an integral role in a number of inflammatory diseases. (1) In this report, we characterize these FR+ macrophages and further investigate whether monocytes, the precursors to these macrophages, also express FR. We demonstrate that FR expression is observed on a subset of highly activated peritoneal and synovial macrophages, but not on other infiltrating immune cells or resident macrophages. We further find that a subset of human peripheral blood monocytes also expresses FR, albeit at a lower level than activated macrophages. Surface antigen characterization of the FR+ monocytes suggests markers characteristic of an inflammatory phenotype (CD14hiCD16), while the resident monocytes (CD14loCD16+) express few or no FR. Preliminary clinical data also suggest that the numbers of peripheral FR+ monocytes can be reduced by a folate-targeted immunotherapy. These results suggest that activated macrophages and inflammatory monocytes express a FR that can be targeted with folate-linked drugs without promoting drug uptake by non-activated macrophages and resident monocytes.
1. Xia W, Hilgenbrink AR, et al. Blood. 2008 Oct 24. [Epub ahead of print]
This work was supported in part by a grant from Endocyte, Inc.
ESM inhibits the production of proinflammatory cytokines in macrophages (92.13)
Authors: Moon Sunhee , Lee Sungwon , Shin Seulmee , Kown Jeonghak , Gong Hyunseok , Lee Seungjeong , Kim Kyungjae 
Published: January 2023

Abstract
Salvia miltiorrhiza (SM) has been commonly used in traditional medicine to treat vascular diseases such as hypertension, arteriosclerosis, and inflammatory disease. It is little kwon that extract of SM alters the immune response of inflammatory reaction. Macrophage, essential cellular components of the body's host defense system, has critical functions in both innate and adoptive system. Macrophages exhibit a particularly vigorous response to endotoxin, which induces production of a variety of inflammatory mediators, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), prostagrandinE2 (PGE2), and nitric oxide (NO) via the inducible nitric oxide synthase (iNOS). In this study, we examined that inhibition effect of ethanol extract of SM (ESM) on pro-inflammatory mediators in LPS-induced murine macrophage cell line RAW 264.7 cells as well as in primary macrophages. ESM deceased the production NO and pro-inflammatory cytokine such as IL-1β, IL-6, TNF-α, and COX-2 in LPS-stimulated macrophage. The variation of gene expression level by ESM treatment was determined by RT-PCR and the relation of mRNA expression of pro-inflammatory cytokine in activated macrophage was suppressed by ESM. In western blot analysis, the level of cytokine protein was decreased in activated macrophage by ESM dose-dependently manner. In addition, the expression of co-stimulatory molecules such as ICAM-1, B7-1, and B7-2 was decreased by ESM dose-dependently. These results showed that ESM has immunomodulatory activities in both innate and adoptive immunity, and they provide the critical information for the understanding of the mechanism of inflammation studies.
Key words: Salvia miltiorrhiza, anti-inflammatory, immunomodulator, cytokines
Oxidative stress-induced protein radical formation precedes follicular dendritic cell apoptosis in murine sepsis (92.3)
Authors: Chatterjee Saurabh , Deterding Leesa , Tucker Jeff , Corbett Jean , Mason Ronald P 
Published: January 2023

Abstract
New studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells including follicular dendritic cells (FDCs). However studies by Hotchkiss et al, and others have shown that FDC's undergo caspase 3-mediated apoptosis at 36 h post sepsis with profound depletion of these cells by 48 hours, but the underlying causes of apoptosis have been unknown. This study hypothesizes the role of oxidative stress-induced protein radical formation in FDCs as the principle cause of apoptosis in murine sepsis. This study utilizes immuno-spin trapping to detect DMPO (spin trap) nitrone adducts in FDCs isolated from Lipopolysaccharide (LPS)-primed mice after flow sorting. The isolated FDCs were also screened by LC/MS/MS analysis to detect possible proteins that contained DMPO nitrone adducts. Results indicated that mice administered LPS had DMPO nitrone adduct formation at 24 hours post sepsis as detected by western blot analysis and confocal microscopy. Mice administered allopurinol mice showed significant decrease in adduct formation, annexin V binding, thus indicating the role of xanthine oxidase in oxidative stress-induced protein radical formation and apoptosis. This clearly suggested a role of xanthine oxidase-mediated oxidative stress in FDC apoptosis in the germinal center of septic mice.
An evaluation of fetal/neonatal and chronic adult ethanol exposure (FNEE and CAEE) on murine cutaneous dendritic cell (CDC) maturation and migration using an organ culture system (92.5)
Authors: Parlet Corey  Patrick , Schlueter Annette J. 
Published: January 2023

Abstract
Alcoholism and fetal alcohol syndrome are associated with increased rates of infection. CDCs, consisting of Langerhans cells (LCs), langerin+ dermal dendritic cells (LdDCs) and langerin - dermal dendritic cells, initiate adaptive immune responses by transporting antigen from the skin to the regional lymph node (RLN). We previously reported a migratory delay of langerin+ CDCs (LCDCs) into the RLN due to CAEE. Migration of CDCs into the RLN is driven by chemokine receptors (CCRs) and adhesion molecules (AMs). To determine if either CAEE or FNEE impair the CCR/AM expression needed for timely transit into the RLN, skin explants were cultured (+/-) CPG & CCL21, and the phenotypes of emigrated CDCs (eCDCs) from control and EtOH exposed mice were evaluated by flow cytometry. CAEE reduced the numbers of emigrated LCs (eLCs). It also reduced CCR7 expression on eLCs and emigrated LdDCs (eLdDCs) and LFA-1 expression on eLdDCs. In contrast, FNEE induced a trend towards increased numbers of eLCs without affecting CCR7 and LFA-1 expression. These findings suggest that diminished CDC migratory capacity is a result of CAEE and not FNEE. The decreased expression of CCR7 and LFA-1 provides a mechanism for the migratory delay exhibited by LCDCs as a result of CAEE and ultimately, a mechanism to explain increased skin infections in alcoholics. Evaluation of additional AMs/CCRs are underway for both models. NIH RO1 AA014405 and AA014406 supported this work.
Synergy of TRIF-dependent TLR3 and MyD88-dependent TLR7 in up-regulating expression of mouse FPR2, a promiscuous G-protein-coupled receptor, in microglial cells (92.9)
Authors: Chen Keqiang , Huang Jian , Gong Wanghua , Dunlop Nancy M. , Cui Youhong , Wang Ji Ming 
Published: January 2023

Abstract
Human G-protein-coupled formyl peptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate leukocyte chemotaxis to a variety of pathogen and host-derived peptides, including amyloid â42, a key causative factor in Alzheimer's disease. In mouse microglial cells, mFPR2 is up-regulated by several TLR ligands, resulting in increased cell response to and endocytosis of A â42 peptide. Since microglial cells may be exposed to multiple TLR agonists under pathological conditions, we investigated the consequence of activating TLR3, whose signaling is dependent on the adaptor TRIF, and TLR7, which signals through MyD88. The TLR3 agonist Poly(I:C) and the TLR7 agonist R837, when used alone, each dose-dependently increased the expression of functional mFPR2 in microglial cells. Combination of suboptional concentrations of Poly(I:C) and R837 showed a marked synergistic effect on induction of mFPR2. We further observed that Poly(I:C) enhanced I êB-á phosphorylation induced by R837. Our results indicate that the TRIF-dependent TLR3 and MyD88-dependent TLR7 cooperate to regulate microglial responses which are known to be involved in brain inflammation and neurodegenerative disease.
Age-related changes in inflammatory gene expression in response to the brain irradiation (93.10)
Authors: Lee Won Hee , Sonntag William E. , Lee Yong Woo 
Published: January 2023

Abstract
The aim of the present study was to determine the effect of aging on the levels of expression of pro-inflammatory mediators in response to irradiation in rat brain. Male F344×BN rats (4, 16, and 24 months old) received either whole brain irradiation with a single dose of 10 Gy γ-rays or sham-irradiation, and were maintained for 4, 8, and 24h post-irradiation. The expression levels of various pro-inflammatory mediators such as cytokines, chemokines, adhesion molecules, and matrix metalloproteinases were analyzed by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). A significant and marked up-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and matrix metalloproteinase-9 (MMP-9) was observed in hippocampal regions isolated from irradiated animals at all ages compared with sham-irradiated controls. On the contrary, the expression levels of pro-inflammatory mediators up-regulated by irradiation were significantly attenuated with age. These results demonstrate that radiation-induced pro-inflammatory responses in the brain are significantly influenced by age. (This work was supported by NINDS R01NS056218)
The sympathetic nervous system regulates the release of anti-inflammatory peptides from salivary glands (93.18)
Authors: Morris Katherine E , St. Laurent Chris D , Hoeve Ryan S , Wickware Jim , Forsythe Paul , Mathison Ron , Befus A Dean 
Published: January 2023

Abstract
Chronic and acute stress have profound effects on inflammation. In rats, allergic inflammation is regulated by the sympathetic nervous system acting on salivary glands. Human asthma is frequently accompanied by salivary gland inflammation. Salivary gland dysfunction in stressed individuals could enhance asthma severity. Salivary gland prohormone SMR1 (submandibular rat-1) is cleaved into two peptides that are anti-inflammatory in rats, mice, dogs, sheep, cats, and human cells in pulmonary inflammation, food allergy, septic shock, pancreatitis, and spinal cord injury. We hypothesized that modulation of the autonomic nervous system would change the expression, processing, and secretion of SMR1 and its peptides.
Rats were injected with saline, isoproterenol, or pilocarpine, or the superior cervical ganglion was excised. Saliva, blood, and tissues were collected and analyzed for SMR1. Adrenergic stimulation caused the majority of SMR1 into be secreted into saliva in 60 min. Removal of the superior cervical ganglion that innervates the salivary glands changed SMR1 protein levels in the salivary glands. SMR1 secretion into saliva in response to acute stress may provide a large pool of SMR1-derived peptide products that mediate anti-inflammatory responses locally and systemically. This research is funded by AllerGen NCE.
Identification and characterization of a potent and selective antagonist of the prostaglandin D2 receptor (94.23)
Authors: Eberhardt Christine , Wright Dale , Gomez Anna , Cook Adam , Doherty George , Corrette Christopher , Hunt Kevin , Clark Christopher , Kim Ganghyeok , Romoff Todd , Delisle Kirk , Hayter Laura , Neale Jason , Dean Brian , Chantry David , Carter Laura , Burgess Laurence E 
Published: January 2023

Abstract
Prostaglandin D2 (PGD2) is a potent lipid mediator released from activated mast cells during allergic responses which exerts its pro-inflammatory effects through the GPCR DP2 also referred to as CRTH2. DP2 is expressed on cells associated with allergic inflammation: TH2 cells, eosinophils, mast cells, and basophils.
We have developed orally bioavailable, potent and selective small molecule antagonists of DP2. One of these compounds, ARRY-060, inhibits binding of PGD2 to DP2 (IC50 = 3 nM) and blocks PGD2-stimulated calcium flux with similar potency. Inhibition was fully surmountable by increasing concentrations of PGD2, consistent with a competitive mode of binding. In primary human basophils treatment with PGD2 stimulated a robust chemotactic response that could be blocked by ARRY-060. Selectivity for DP2 was examined by profiling against related prostanoid receptors and no inhibition of these targets was observed, including DP1. In a guinea pig asthma model, ARRY-060 (50 mg/kg, po) decreased total cellular influx in bronchial alveolar lavage. Together, these results support the development of DP2 inhibitors for the treatment of allergic disease.
Loss of Fcgamma receptors ameliorates initiation and progression of atherosclerosis in hyperlipidemic mouse model (94.24)
Authors: Nagarajan Shanmugam 
Published: January 2023

Abstract
OxLDL generated during hyperlipidemia is known to induce an autoimmune response resulting in the production of anti-oxLDL IgG. In humans and in the hyperlipidemic mouse model, the titer of autoantibodies against oxLDL correlates with the progression of atherosclerosis. Although the presence of anti-oxLDL IgG is well documented, the contribution of FcγRs to the initiation and/or progression of atherosclerosis has not been studied in detail. First, to address the presence of oxLDL-IC in atherosclerotic lesions, descending aorta from wild type (WT) and apoE-/- mice fed chow diet for 18 weeks and oxLDL-IC in the lysates were determined. OxLDL-IC was detected in the aortic lysates of both WT and apoE-/- mice. However, the levels were elevated about 8 fold in apoE-/- mice. The presence of anti-oxLDL IgG in atherosclerotic lesions in patients and animal models, suggests the possibility of oxLDL-IC deposition in the lesions. To determine the role of FcγRs in the initiation and/or progression of atherosclerosis, we have generated apoE-/-γ-chain-/- mice by mating γ-chain-/- mice with apoE-/- mice. ApoE-/- and apoE-/-γ-chain-/- mice (age 4 wk) were fed chow diet for 20 weeks. Plasma cholesterol levels were similar in apoE-/- and apoE-/-γ-chain-/- mice. Atherosclerotic lesions in aortic sinus were determined by staining cryosections with Oil Red O. Enface analysis of the descending aorta was performed by staining descending aorta from the aortic arch to the iliac bifurcation with Sudan IV. Both analyses showed about a 50% reduction in lesions in apoE-/-γ-chain-/- mice compared to apoE-/- mice. These novel findings suggest activating FcγRs contribute to the progression of atherosclerosis. (Supported by NIH HL086674).
Sphingosine kinase-1 mediates TNF activation of the integrin VLA-5 for leukocyte adhesion (94.26)
Authors: Bonder Claudine S , Sun Wai Y 
Published: January 2023

Abstract
For leukocyte recruitment to sites of inflammation the classical paradigm states that selectins (eg P- and E-selectin) are important for initial tethering and rolling with subsequent interaction via integrins and cellular adhesion molecules (eg α4β1, VCAM-1 and ICAM-1) enabling their adhesion and emigration from the microvasculature. Previous studies have shown that the lipid enzyme sphingosine kinase-1 (SK-1) is essential for TNFα-induced E-selectin, VCAM-1 and ICAM-1 expression on endothelial cells (EC). However, its role in regulating the expression of other key adhesion molecules is still unclear.
Herein we demonstrate that TNFα activates the integrin VLA-5 (α5β1) without altering total expression levels on human umbilical vein ECs. Moreover, inhibition studies with an SK-1 mutant suggest that TNFα-induced β1 activation is SK-1 dependent. Finally, a parallel plate flow chamber assay suggests that leukocyte adhesion to the TNFα-treated endothelium under shear stress can be attenuated by blocking VLA-5 or its ligand angiopoitein-2 on the ECs.
Taken together, these results suggest that TNFα-induced activation of VLA-5 is SK-1 dependent and mediates, in part, leukocyte adhesion to the endothelium. Given that excessive leukocyte recruitment during inflammation results in chronic and fatal diseases, the regulation of integrins such as VLA-5 is key for developing successful therapeutics to alleviate disease.
This work was supported by an NHMRC Project Grant, Florey Fellowship and Arthritis Australia.
Increased death receptor-induced apoptosis in ezrin-deficient type I T cells (94.28)
Authors: Lai Ming-Zong , Kuo Wen-Chih 
Published: January 2023

Abstract
Ezrin is reported to be essential for Fas-induced apoptosis. Here we showed that ezrin interacts with Fas, yet knockdown of ezrin increased Fas- and TRAIL-induced apoptosis in type I T cells like H9. Expression of the dominant negative form of ezrin also led to increased Fas- and TRAIL-triggered cell death in H9 cells. Similarly, downregulation of ezrin in normal human T lymphocytes resulted in elevated Fas-stimulated cell death. In contrast, ezrin knockdown in type II cells, including Jurkat and CEM cells, did not affect Fas- and TRAIL-induced apoptosis. Ezrin knockdown led to an accelerated caspase-8 activation and enhanced activation of caspase-3 in H9 cells. Ezrin deficiency did not affect the internalization of Fas after Fas engagement in H9 cells. Instead, an enhanced formation of DISC was observed in H9 cells with ezrin knockdown. Together, our results suggest that ezrin plays a negative role in the recruitment of Fas into signaling complex in type I T cells, and deficiency in ezrin removes the constraint imposed by ezrin and facilitates the assembly of death receptor.
Mechanism of platelet adhesion to neutrophils in sepsis (94.3)
Authors: Urrutia Rossana , Ma Adrienne C. , Kubes Paul 
Published: January 2023

Abstract
Sepsis is a systemic inflammatory response to infection which has a high mortality rate in the intensive care unit (ICU) resulting in 215000 deaths a year in United States. Neutrophils and platelets play an important role in the induction of inflammation and defense against infection in this pathology. Recent studies by our group have revealed that in severe sepsis TLR4 stimulated platelets interact with already adherent neutrophils. This interaction leads to the formation of Neutrophil Extracellular Traps (NETs) in the circulation, which helps to enhance bacterial trapping and clearance from the body; however, this may also enhance host injury in the liver sinusoids and pulmonary capillaries. To further elucidate the mechanisms by which activated platelets can adhere to immobilized neutrophils in the setting of sepsis, we used an in vitro flow chamber system using LPS and septic plasma as platelet stimulants. Antibodies to several adhesion molecules on platelets and neutrophils were tested. TLR4 activated platelets did not express P-Selectin on their surface and their interaction with immobilized neutrophils was not P-selectin-dependent. Findings show that LFA-1 and CD11c/CD18 on neutrophils, and JAM-A and ICAM-2 on platelets are involved in LPS-induced platelet adhesion to immobilized neutrophils. In addition, results from septic plasma stimulated platelets show that LFA-1 and CD11c/CD18, but not JAM-A, are involved in platelet adhesion to immobilized neutrophils. Blocking the adhesion molecules that take place in platelet adhesion to immobilized neutrophil could prevent NET formation and tissue damage specifically in lungs and liver capillaries providing a target for new therapeutics in this pathology.
Thromboxane A2 receptor regulates the severity of experimental murine colitis (94.30)
Authors: Dann Sara , Ditto David , Spehlmann Martina , Kagnoff Martin , Le Dzung , Eckmann Lars 
Published: January 2023

Abstract
Background: Prostanoids, lipid mediators of the COX pathway, are elevated in inflammatory bowel disease and are regulators of intestinal inflammation, yet the roles of individual prostanoids are poorly understood. We evaluated the role of the prostanoid thromboxane A2 (TXA2) in a murine model of colitis. Methods: Colitis was induced by feeding DSS to mice lacking the receptor for TXA2 and their normal littermate controls. Disease severity was analyzed by clinical and histological parameters. Production of TXA2 and expression of its synthases were determined by ELISA and real-time RT-PCR, respectively. Platelet aggregation was assessed using collagen and TXA2 receptor antagonist, and activation was measured by the release of platelet factor 4 (PF4/CXCL4). Results: Our results show that expression of COX-2 and TXA2 were increased in colitis. Mice lacking the TXA2 receptor showed attenuated intestinal inflammation and ulceration, and were protected against colitis-associated weight loss and mortality. Platelet aggregation responses were enhanced in colitic animals. Activation led to increased levels of PF4, which enhanced CXCL1 (KC) induced migration of neutrophils. Conclusions: These results indicate that TXA2 promotes colitis through activation of platelets and augmentation of neutrophil recruitment. Therefore, blockade of the TXA2 system maybe of therapeutic value in intestinal inflammation.