Abstract 179: TLR3 Deficiency Attenuates Preeclampsia-Like Symptoms in Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Piyali Chatterjee ◽  
Valorie L Chiasson ◽  
Shelley E Kopriva ◽  
Laura E Weaver ◽  
Brett M Mitchell
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune System ◽  
Endothelial Dysfunction ◽  
Immune Cells ◽  
Γδ T Cells ◽  
Poly I:C ◽  
Fetal Demise ◽  
Immune System Activation ◽  
System Activation

Preeclampsia (PE), diagnosed by hypertension and proteinuria at or after the 20 th week of gestation, is mediated in part by excessive immune system activation and inflammation. Ligand binding of the double-stranded RNA (dsRNA) receptors RIG-1, MDA-5, and TLR3 leads to innate immune system activation and inflammation. However, whether activation of all three receptors contributes to the development of PE is unknown. In placentas of women with PE there was significantly increased expression of all three dsRNA receptors as well as dsRNA compared to placentas of normotensive women. Poly I:C (a viral dsRNA mimetic) treatment in control mice on days 13, 15, and 17 induced pregnancy-dependent hypertension (P-PIC SBP: 147±5 mmHg vs. P SBP: 100±4 mmHg, p<0.05), endothelial dysfunction, fetal demise and altered immune cell subsets. This was associated with increased placental protein levels of all three dsRNA receptors compared to normal pregnant mice (RIG-1: 47%, MDA-5: 59%, and TLR3: 86%, p<0.05 vs. controls). Splenic levels of the anti-inflammatory immune cells CD4+/CD25+ regulatory T cells (Tregs) and CD11b+/CD14- myeloid-derived suppressor cells (MDSCs) decreased significantly while the pro-inflammatory immune cells CD11b+ monocytes, CD3+/γδ T cells, and CD11c+ dendritic cells were increased significantly in P-PIC compared to P mice. In pregnant, poly I:C-treated TLR3KO mice SBP was decreased significantly compared to P-PIC mice but not fully restored (P-PIC TLR3KO: 110±3 mmHg). P-PIC TLR3KO mice exhibited significantly reduced endothelial dysfunction and fetal demise compared to P-PIC mice, as well as significantly increased splenic CD4+/CD25+ Tregs and CD11b+/CD14- MDSCs and decreased CD11b+ monocytes, CD3+/γδ T cells, and CD11c+ dendritic cells. These results taken together suggest that activation of dsRNA receptors contribute to the development of PE-like symptoms in mice, but TLR3 deficiency alone did not completely prevent PE-like symptoms. Thus, RIG-1 and MDA-5 activation may play a partial role in blood pressure regulation during pregnancy.

Abstract 095: CD74 Deficient Mice are Resistant to Toll-Like Receptor-Induced Preeclampsia

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Mohamad Hatahet ◽  
Olga Y Gasheva ◽  
Valorie L Chiasson ◽  
Piyali Chatterjee ◽  
Kelsey R Bounds ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Endothelial Dysfunction ◽  
Mhc Class Ii ◽  
Immune Cells ◽  
Immune Cell ◽  
Class Ii ◽  
Poly I:C ◽  
Hypertensive Disorder ◽  
Toll Like Receptor

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by vascular endothelial dysfunction and excessive immunity and inflammation. Activation of the dsRNA receptor Toll-like receptor 3 (TLR3) or the ssRNA receptor TLR7 elicits a pregnancy-dependent PE-like syndrome in mice by inducing a pro-inflammatory immune response. CD74 (MHC Class II invariant chain) acts as a chaperone for MHC Class II surface expression on immune cells during antigen presentation and is cleaved into Class II-Associated Invariant Peptide (CLIP) following polyclonal activation of immune cell TLRs. The presence of CLIP in the groove of MHC Class II prevents T cell-dependent death leading to persistent immune cell activation. We hypothesized that genetic deletion of CD74 and subsequent depletion of CLIP on immune cells prevents TLR-induced immune responses and the development of PE in mice. Pregnant WT and CD74 KO mice were given i.p. injections of normal saline (P), poly I:C (TLR3 agonist; P-PIC), or R837 (TLR7 agonist; P-R837) on gestational days 13, 15, and 17 and euthanized on day 18. P-PIC and P-R837 WT mice had significantly increased splenic levels of pro-inflammatory CD3+/gd T cells and plasma levels of the gd T cell-derived cytokines IFNg, TNFa, and IL-17 compared to P WT mice whereas P-PIC and P-R837 CD74 KO mice had significantly increased anti-inflammatory CD3+/gd T cells and no significant increases in plasma IFNg, TNFa, and IL-17 levels. P-PIC and P-R837 CD74 KO mice did not develop the hypertension (gd17 SBP in mmHg: P WT=102±3, P CD74 KO=100±3, P-PIC WT=147±4*, P-PIC CD74 KO=95±3, P-R837 WT=133±2*, P-R837 CD74 KO=97±1; *p<0.05 vs. P WT), endothelial dysfunction, proteinuria, or placental necrosis seen in P-PIC and P-R837 WT mice. In conclusion, CD74 is crucial for the development of TLR-induced PE-like symptoms in mice and CD74/CLIP depletion may be a promising therapeutic target for women with PE.

Abstract P145: Renal Inflammation and Injury is Associated with Increased Lymphangiogenesis in Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sterling C Kneedler ◽  
Lauren Phillips ◽  
Kayla R Hudson ◽  
Katharine M Beckman ◽  
Alan R Parrish ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Immune System ◽  
Immune Cells ◽  
Lymphatic Vessels ◽  
Macrophage Infiltration ◽  
Shr Rats ◽  
Renal Inflammation ◽  
Immune System Activation ◽  
System Activation ◽  
Fischer Rats

Hypertension is associated with immune system activation and inflammation. Renal infiltration of both innate and adaptive immune cells contributes to injury, dysfunction, and increased blood pressure. Activated immune cells that exit blood vessels into the interstitium then travel through lymphatic vessels to draining lymph nodes where they signal to other immune cells to increase the immune response. It is unknown how renal lymphatic vessels change in the context of hypertension, immune system activation, inflammation, and injury. We hypothesized that renal macrophage infiltration, inflammation, and injury would significantly increase lymphangiogenesis in various strains of rats. SHR rats that exhibit hypertension and renal injury (SHR-A3 strain) had significantly increased numbers of renal lymphatic vessels at 40 weeks of age compared to WKY controls (total of 3 fields of view: 52 ± 1 vs. 28 ± 1; p<0.05). This was associated with increased renal macrophage infiltration. SHR rats that exhibit hypertension but minimal renal injury (SHR-B2 strain) had significantly less renal lymphatic vessel numbers compared to WKY controls (25 ± 2 vs. 28 ± 1; p<0.05) and normal levels of macrophages. The signals for lymphangiogenesis, VEGF-C and its receptor VEGF-R3, were both increased significantly at the protein level in the kidneys of SHR-A3 rats at 18 weeks but not different in the kidneys of SHR-B2 rats compared to WKY controls. To test whether the increased lymphangiogensis is due to hypertension and/or renal inflammation and injury, we obtained kidneys from Fischer 344 rats that exhibit normal blood pressure but develop renal inflammation and injury as they age. Compared to kidneys from control 4-month old Fischer rats, kidneys from 20-month and 24-month old Fischer rats had significantly increased numbers of lymphatic vessels (32 ± 3 vs. 74 ± 1 vs. 110 ± 6, respectively; p<0.05) and this was also associated with increased macrophage infiltration. Protein levels of VEGF-C and VEGF-R3 were increased significantly in 20-month old Fischer rats compared to 4-month old controls. These data together demonstrate that renal immune cell infiltration, inflammation, and injury increases lymphangiogenesis.

Breast Cancer Multi-therapy and Immune System Activation, Checkpoint Modulators, Signal Inhibitors and T Cells Reprogramming

2019 ◽  
Author(s):  
Miguel A Galván Morales ◽  
Raúl Barrera Rodríguez ◽  
Julio R. Santiago Cruz ◽  
Luis M Terán Juárez
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Immune System ◽  
Immune System Activation ◽  
System Activation

Interferon-γ Mediated Pathways And Mitogen Stimulated Proliferation During And After An Acute Infection

Pteridines ◽  
2018 ◽  
Vol 29 (1) ◽  
pp. 70-79
Author(s):  
Miriam Knoll ◽  
Dietmar Fuchs ◽  
Guenter Weiss ◽  
Rosa Bellmann-Weiler ◽  
Bojana Kovrlija ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Bacterial Infections ◽  
Acute Infection ◽  
Interferon Γ ◽  
Immune System Activation ◽  
System Activation ◽  
Acute Bacterial Infections

AbstractBackground: Interferon-γ (IFN- γ) regulates the degradation of tryptophan to kynurenine via induction of indoleamine- 2,3-dioxygenase (IDO). Local tryptophan depletion and accumulation of toxic metabolites might impair the proliferative capacity of lymphocytes. The aim of this study was to assess the actual status of immune system activation of patients with bacterial infection in the acute phase and during convalescence in vivo and in vitro. Parameters of systemic immune system activation were evaluated for associations with proliferative responsiveness of immune cells, and compared with healthy controls. Methods: 24 patients with various acute bacterial infections were included in the group of acutely ill patients. Sixteen patients participated in a follow-up examination after convalescence. The control group consisted of 6 healthy people. To assess the status of immune system activation in vivo, inflammation parameters C-reactive protein and differential blood counts were determined. Neopterin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Tryptophan and kynurenine measurements were performed with high pressure liquid chromatography (HPLC). Peripheral blood mononuclear cells (PBMCs) were isolated from the patients’ blood and stimulated with concanavalin A (Con A), phytohemagglutinin (PHA) and pokeweed mitogen (PWM) in vitro proliferation rates were evaluated by ³H-thymidine incorporation and neopterin production and tryptophan degradation were determined in supernatants of mitogen stimulated PBMCs. Results: Patients with acute bacterial infections showed reduced tryptophan and elevated neopterin concentrations, which did not normalize after convalescence period. Higher plasma neopterin values and increased IDO-activity were associated with reduced proliferative responses in vitro after stimulation with PHA. Associations were observed during acute infection as well as convalescence. Conclusions: Results of this study show that increased immune system activation in vivo is associated with impaired proliferative responsiveness of immune cells in vitro in acute bacterial infections as well as during convalescence.

scholarly journals High Dose Vardenafil Blunts the Hypertensive Effects of Toll-Like Receptor 3 Activation During Pregnancy

2021 ◽  
Vol 1 ◽  
Author(s):  
Dakshnapriya Balasubbramanian ◽  
Sathish Dharani ◽  
Mohammad Tauseef ◽  
Mansoor A. Khan ◽  
Ziyaur Rahman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Immune System ◽  
Innate Immune System ◽  
Low Dose ◽  
Innate Immune ◽  
Poly I:C ◽  
High Dose ◽  
Fetal Demise ◽  
Immune System Activation ◽  
Similar Drug

The maternal innate immune system plays a central role in preeclampsia (PE). Toll-like receptors (TLRs) are innate immune system receptors that recognize characteristics of extracellular endogenous ligands or pathogens, and their activation leads to a pro-inflammatory immune response. We and others have reported that excessive activation of TLRs causes pregnancy-dependent hypertension in animals and is associated with PE in women. Activation of TLR3 by poly I:C mimics the innate immune system activation by viruses that women who develop PE encounter during pregnancy. Vardenafil was approved by the FDA for erectile dysfunction but has recently been examined as a potential PE medication due to studies done with a similar drug, sildenafil. Preclinical as well as recent clinical studies demonstrate the potential effectiveness of sildenafil for PE. However, vardenafil is more potent than sildenafil and acts by increasing expression of placental growth factor in addition to increasing cGMP levels. We hypothesized that vardenafil will be more potent and effective in reducing the negative health effects in a mouse model of virus-induced PE. Pregnant mice were injected with the TLR3 agonist poly I:C (PPIC) on gestational days 13, 15, and 17. We treated PPIC mice with a high dose of vardenafil (50 mg human equivalent), a lower dose of vardenafil (20 mg human equivalent), or sildenafil (50 mg human equivalent) on gestational days 15–17 after hypertension was established. Daily i.p. injections of either high dose or low dose vardenafil significantly decreased systolic blood pressure in PPIC mice whereas sildenafil had no effect. There were no differences in body weight between the groups. The splenomegaly induced in PPIC mice was ameliorated in high dose vardenafil-treated PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still exhibited splenomegaly. High dose vardenafil-treated PPIC mice also did not exhibit any fetal demise characteristic of PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still had significantly increased incidences of fetal demise. These data support the notion that high dose vardenafil may be safe and effective at reducing blood pressure during a virus-associated hypertensive pregnancy.

scholarly journals Distinct hepatic myeloid and lymphoid cell repertoires are associated with susceptibility and resistance to Ascaris infection

Parasitology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Gwendoline Deslyper ◽  
Dearbhla M. Murphy ◽  
Oluyomi A. Sowemimo ◽  
Celia V. Holland ◽  
Derek G. Doherty
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune System ◽  
Mouse Model ◽  
Immune Cells ◽  
Mouse Strains ◽  
Cell Counts ◽  
Nk T Cells ◽  
Susceptibility And Resistance

Abstract The soil-transmitted helminth Ascaris lumbricoides infects ~800 million people worldwide. Some people are heavily infected, harbouring many worms, whereas others are only lightly infected. The mechanisms behind this difference are unknown. We used a mouse model of hepatic resistance to Ascaris, with C57BL/6J mice as a model for heavy infection and CBA/Ca mice as a model for light infection. The mice were infected with the porcine ascarid, Ascaris suum or the human ascarid, A. lumbricoides and immune cells in their livers and spleens were enumerated using flow cytometry. Compared to uninfected C57BL/6J mice, uninfected CBA/Ca mice had higher splenic CD4+ and γδ T cell counts and lower hepatic eosinophil, Kupffer cell and B cell counts. Infection with A. suum led to expansions of eosinophils, Kupffer cells, monocytes and dendritic cells in the livers of both mouse strains and depletions of hepatic natural killer (NK) cells in CBA/Ca mice only. Infection with A. lumbricoides led to expansions of hepatic eosinophils, monocytes and dendritic cells and depletions of CD8+, αβ, NK and NK T cells in CBA/Ca mice, but not in C57BL/6J mice where only monocytes expanded. Thus, susceptibility and resistance to Ascaris infection are governed, in part, by the hepatic immune system.

scholarly journals Balloon cells promote immune system activation in focal cortical dysplasia type 2B

2021 ◽  
Author(s):  
Till S. Zimmer ◽  
Diede W.M. Broekaart ◽  
Mark Luinenburg ◽  
Caroline Mijnsbergen ◽  
Jasper J. Anink ◽  
...  
Keyword(s):  
Immune System ◽  
Focal Cortical Dysplasia ◽  
Cortical Dysplasia ◽  
Balloon Cells ◽  
Immune System Activation ◽  
System Activation

scholarly journals The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian-Yu Lei ◽  
Ying-Ze Ye ◽  
Xi-Qun Zhu ◽  
Daniel Smerin ◽  
Li-Juan Gu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Ischaemic Stroke ◽  
Immune Cells ◽  
Tissue Injury ◽  
Recovery Period ◽  
Vital Functions ◽  
Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

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