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

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.

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

Pteridines ◽

10.1515/pteridines-2018-0005 ◽

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.

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Abstract P339: Genetically Induced Renal Lymphangiogenesis Prevents the Development of L-NAME Hypertension in Mice

Hypertension ◽

10.1161/hyp.70.suppl_1.p339 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Catalina A Lopez Gelston ◽

Dakshnapriya Balasubbramanian ◽

Gabriella R Abouelkheir ◽

Alexandra H Lopez ◽

Kayla R Hudson ◽

...

Keyword(s):

Gene Expression ◽

Blood Pressure ◽

Drinking Water ◽

Immune Cells ◽

Lymphatic Vessel ◽

Lymphatic Vessels ◽

Vessel Density ◽

Lymphatic Vessel Density ◽

Cell Marker ◽

Immune System Activation

In humans and experimental animals, persistent immune system activation, accumulation of immune cells in the kidney, and subsequent inflammation plays an essential role in the development of hypertension (HTN). To reduce inflammation, lymphatic vessels drain extracellular fluid from the interstitium and traffic immune cells to draining lymph nodes. However, little is known about the connection between hypertension and renal lymphatic vessels. We hypothesized that renal lymphatic vessel density would increase in mice with L-NAME HTN and that genetically induced renal lymphangiogenesis would prevent this increase in blood pressure. L-NAME (0.5 mg/mL) was administered in the drinking water for two weeks and caused HTN (SBP: 153±3 vs. 103±3 mmHg; p<0.05) and renal lymphatic vessel dilation compared to control mice. Kidneys from mice with L-NAME HTN had significantly increased gene expression of the lymphangiogenic marker Vegfc , macrophage marker Adgre1 (F4/80), dendritic cell marker Cd11c , Th1 cell marker Tbx21 , and the pro-inflammatory cytokine Il6 . Blood pressure decreased after a two-week washout period following L-NAME (SBP: 113±2 mmHg) which was associated with a decrease in renal gene expression of Adgre1 (F4/80) and Cd11c , however renal lymphatic vessels remained dilated. To determine if augmenting renal lymphatic vessel density prior to L-NAME treatment would prevent HTN, we used transgenic mice that in response to doxycycline undergo kidney-specific VEGF-D overexpression (KidVD+ mice) and renal lymphangiogenesis. Doxycycline (200 mg/L) was administered in the drinking water of KidVD+ and KidVD- mice for four weeks with L-NAME being added during the final three weeks. Starting doxycycline one week prior to L-NAME prevented HTN in KidVD+ mice while slightly decreasing SBP in KidVD- mice (SBP: 112±4 vs. 134±2 mmHg; p<0.05). Renal gene expression of the Th17 cell marker Rorc was decreased and the lymphatic chemokine markers Ccl21 and Ccl19 were increased significantly in KidVD+ mice. These data together demonstrate that L-NAME HTN can alter the size of renal lymphatic vessels and genetically augmenting renal lymphatic vessel density prior to L-NAME can prevent the development of HTN.

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

Hypertension ◽

10.1161/hyp.60.suppl_1.a179 ◽

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.

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

Neuropathology and Applied Neurobiology ◽

10.1111/nan.12736 ◽

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

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Posterior Reversible Encephalopathy Syndrome (PRES) With Immune System Activation, VEGF Up-Regulation, and Cerebral Amyloid Angiopathy

Journal of Computer Assisted Tomography ◽

10.1097/rct.0b013e3181f31917 ◽

2011 ◽

Vol 35 (1) ◽

pp. 39-42 ◽

Cited By ~ 18

Author(s):

Julia Kofler ◽

Walter S. Bartynski ◽

Thomas Q. Reynolds ◽

Frank S. Lieberman ◽

Geoffrey H. Murdoch ◽

...

Keyword(s):

Immune System ◽

Cerebral Amyloid Angiopathy ◽

Posterior Reversible Encephalopathy Syndrome ◽

Amyloid Angiopathy ◽

Posterior Reversible Encephalopathy ◽

Immune System Activation ◽

System Activation ◽

Cerebral Amyloid ◽

Reversible Encephalopathy

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Expression of Phosphocitrate-Targeted Genes in Osteoarthritis Menisci

BioMed Research International ◽

10.1155/2014/210469 ◽

2014 ◽

Vol 2014 ◽

pp. 1-17 ◽

Cited By ~ 5

Author(s):

Yubo Sun ◽

David R. Mauerhan ◽

Nury M. Steuerwald ◽

Jane Ingram ◽

Jeffrey S. Kneisl ◽

...

Keyword(s):

Immune System ◽

Molecular Mechanisms ◽

Fibroblast Growth Factor Receptor ◽

Collagen Type ◽

Skeletal Development ◽

Growth Factor Receptor ◽

Type Ii ◽

Immune System Activation ◽

System Activation ◽

Disease Modifying

Phosphocitrate (PC) inhibited calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms remain elusive. This study sought to determine PC targeted genes and the expression of select PC targeted genes in OA menisci to test hypothesis that PC exerts its disease modifying activity in part by reversing abnormal expressions of genes involved in OA. We found that PC downregulated the expression of numerous genes classified in immune response, inflammatory response, and angiogenesis, including chemokine (C-C motif) ligand 5, Fc fragment of IgG, low affinity IIIb receptor (FCGR3B), and leukocyte immunoglobulin-like receptor, subfamily B member 3 (LILRB3). In contrast, PC upregulated the expression of many genes classified in skeletal development, including collagen type II alpha1, fibroblast growth factor receptor 3 (FGFR3), and SRY- (sex determining region Y-) box 9 (SOX-9). Immunohistochemical examinations revealed higher levels of FCGR3B and LILRB3 and lower level of SOX-9 in OA menisci. These findings indicate that OA is a disease associated with immune system activation and decreased expression of SOX-9 gene in OA menisci. PC exerts its disease modifying activity on OA, at least in part, by targeting immune system activation and the production of extracellular matrix and selecting chondroprotective proteins.

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