scholarly journals Modulation of Immune-Inflammatory Responses in Abdominal Aortic Aneurysm: Emerging Molecular Targets

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Hanrong Li ◽  
Shuling Bai ◽  
Qiang Ao ◽  
Xiaohong Wang ◽  
Xiaohong Tian ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Immune System ◽  
Aortic Aneurysm ◽  
Innate Immune System ◽  
Chemokine Receptors ◽  
Inflammatory Cell ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Innate Immune ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA), a deadly vascular disease in human, is a chronic degenerative process of the abdominal aorta. In this process, inflammatory responses and immune system work efficiently by inflammatory cell attraction, proinflammatory factor secretion and subsequently MMP upregulation. Previous studies have demonstrated various inflammatory cell types in AAA of human and animals. The majority of cells, such as macrophages, CD4+ T cells, and B cells, play an important role in the diseased aortic wall through phenotypic modulation. Furthermore, immunoglobulins also greatly affect the functions and differentiation of immune cells in AAA. Recent evidence suggests that innate immune system, especially Toll-like receptors, chemokine receptors, and complements are involved in the progression of AAAs. We discussed the innate immune system, inflammatory cells, immunoglobulins, immune-mediated mechanisms, and key cytokines in the pathogenesis of AAA and particularly emphasis on a further trend and application of these interventions. This current understanding may offer new insights into the role of inflammation and immune response in AAA.

Inflammatory Cells and Proteases in Abdominal Aortic Aneurysm and its Complications

2018 ◽  
Vol 19 (11) ◽  
pp. 1289-1296 ◽  
Author(s):  
Haiying Jiang ◽  
Takeshi Sasaki ◽  
Enze Jin ◽  
Masafumi Kuzuya ◽  
Xian Wu Cheng
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
Abdominal Aortic

scholarly journals Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 460
Author(s):  
Saray Varona ◽  
Lídia Puertas ◽  
María Galán ◽  
Mar Orriols ◽  
Laia Cañes ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
Progressive Increase ◽  
Phosphodiesterase 4 ◽  
Inflammatory Conditions ◽  
Abdominal Aortic ◽  
Threatening Condition ◽  
Life Threatening ◽  
Effective Therapeutic Strategy

Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA.

scholarly journals SM22α Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage-Derived circRasGEF1B

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Pin Lv ◽  
Ya-Juan Yin ◽  
Peng Kong ◽  
Li Cao ◽  
Hao Xi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Inflammatory Cell ◽  
Activated Macrophages ◽  
Abdominal Aortic ◽  
Specific Manner ◽  
Higher Sensitivity

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α-/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM ( P < 0.01 ), and apoptosis of Sm22α-/- VSMCs was higher than that of WT VSMCs ( P < 0.001 ). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α-/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α-/- VSMCs have a higher sensitivity to apoptosis.

scholarly journals Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans

2018 ◽  
Vol 104 (4) ◽  
pp. 1187-1199 ◽  
Author(s):  
Ahmed Iqbal ◽  
Lynne R Prince ◽  
Peter Novodvorsky ◽  
Alan Bernjak ◽  
Mark R Thomas ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Immune System ◽  
Innate Immune System ◽  
Low Dose ◽  
Inflammatory Responses ◽  
Platelet Reactivity ◽  
Innate Immune ◽  
Endotoxin Challenge ◽  
Intermediate Monocytes

Abstract Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P &lt; 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P &lt; 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P &lt; 0.01; vs sham-saline 26.20 ± 3.86/μL, P &lt; 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P &lt; 0.001; vs sham-saline 19.05 ± 3.81/μL, P &lt; 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P &lt; 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P &lt; 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P &lt; 0.05; vs sham-saline 3.81± 1.42/μL, P &lt; 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P &lt; 0.01; vs sham-saline 3.08 ± 1.01/μL, P &lt; 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P &lt; 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.

Abstract 260: Identification of Micrornas Specifically Expressed in Isolated Cells of Human Abdominal Aortic Aneurysm

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Florence Pinet ◽  
Rafaelle Spear ◽  
David Hot ◽  
Bart Staels ◽  
Maggy Chwastyniak ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
The Elderly ◽  
M2 Macrophages ◽  
Isolated Cells ◽  
Human Mirnas ◽  
Specific Distribution ◽  
Abdominal Aortic ◽  
M1 And M2 Macrophages

Abdominal aortic aneurysm (AAA) is a vascular asymptomatic disease responsible for 4% of mortality in the elderly population. MicroRNAs (miRNA) have recently been shown to be potential biomarkers due to their stability in plasma. The aim of this study was to investigate the potentiality of miRNAS as biomarkers of AAA by identifying miRNAs specifically expressed in the key cells present in the human AAA tissue. The distribution of inflammatory cells such as smooth muscle cells (SMC), M1 and M2 macrophages, neutrophils, B and T lymphocytes and mast cells were located by immunohistochemistry in 20 human AAA biopsies, showing a specific distribution towards the aneurysmal aortic wall and the presence of adventitial tertiary lymphoid organs (ATLOs) in 10 samples. We isolated by laser microdissection (LMD) area enriched in aneurysmal SMC, M1 and M2 macrophages, and ATLOs and SMC from control aorta. RNA extracted from 2 samples of LMD-isolated cells was screened on human miRNAs microarray. Out of the 850 human miRNAs, more than 200 miRNAs were detected in LMD-isolated aneurysmal cells, with 164 detected in ATLOs, 49 in SMC, and 87 miRNAs in macrophages. We selected the 3 miRs with the highest expression for ATLOs and 10 miRs (based on their miR-29b levels) for SMC and macrophages for validation by qRT-PCR in LMD-isolated samples (n=4). We found that miR-15a-3p (0.1 fold) and miR-30a-5p (0.2 fold) were down-regulated and miR-489-3p up-regulated (2 fold) in ATLOs which was inversed for miR-489-3p in the whole aneurysmal aorta. Of the 10 miRNAs selected, six (miR-199a-3p and miR-451 upregulated and miR-24, miR-29a, miR-29b, and miR-29c downregulated) were modulated similarly in SMC and macrophages and whole aneurysmal aorta, except for miR-199-3p. Let-7f and miR-34a were similarly upregulated ed in both subtypes of macrophages and aneurysmal aorta. Expression in the plasma of AAA (n=24) compared to PAD (n=18) patients was significantly down-regulated for miR-15a-3p (p = 0.03) and miR-30a-5p (p = 0.04) and upregulated for let-7f (p=0.048) and miR-29b (p=0.035). In conclusion, this non-hypothesis driven screening of miRNAs expressed in isolated aneurysmal cells allowed to identify four miRNAs as potential AAA biomarkers.

scholarly journals Bcr and Abr Cooperate in Negatively Regulating Acute Inflammatory Responses

2009 ◽  
Vol 29 (21) ◽  
pp. 5742-5750 ◽  
Author(s):  
Jess M. Cunnick ◽  
Sabine Schmidhuber ◽  
Gang Chen ◽  
Min Yu ◽  
Sun-Ju Yi ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Small Gtpase ◽  
Innate Immune ◽  
Ros Production ◽  
Activated Neutrophils ◽  
Inflammatory Processes ◽  
Null Mutant Mice

ABSTRACT Bcr and Abr are GTPase-activating proteins for the small GTPase Rac. Both proteins are expressed in cells of the innate immune system, including neutrophils and macrophages. The function of Bcr has been linked to the negative regulation of neutrophil reactive oxygen species (ROS) production, but the function of Abr in the innate immune system was unknown. Here, we report that mice lacking both proteins are severely affected in two models of experimental endotoxemia, including exposure to Escherichia coli lipopolysaccharide and polymicrobial sepsis, with extensive microvascular leakage, resulting in severe pulmonary edema and hemorrhage. Additionally, in vivo-activated neutrophils of abr and bcr null mutant mice produced excessive tissue-damaging myeloperoxidase (MPO), elastase, and ROS. Moreover, the secretion of the tissue metalloproteinase MMP9 by monocytes and ROS by elicited macrophages was abnormally high. In comparison, ROS production from bone marrow monocytes was not significantly different from that of controls, and the exocytosis of neutrophil secondary and tertiary granule products, including lactoferrin, was normal. These data show that Abr and Bcr normally curb very specific functions of mature tissue innate immune cells, and that each protein has distinct as well as partly overlapping functions in the downregulation of inflammatory processes.

scholarly journals A Novel Hypothesis: A Role for Follicle Stimulating Hormone in Abdominal Aortic Aneurysm Development in Postmenopausal Women

2021 ◽  
Vol 12 ◽  
Author(s):  
Victoria N. Tedjawirja ◽  
Max Nieuwdorp ◽  
Kak Khee Yeung ◽  
Ron Balm ◽  
Vivian de Waard
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Postmenopausal Women ◽  
Cholesterol Biosynthesis ◽  
Follicle Stimulating Hormone ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Menopausal Transition ◽  
Abdominal Aortic ◽  
Stimulating Hormone

An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta, which can potentially be fatal due to exsanguination following rupture. Although AAA is less prevalent in women, women with AAA have a more severe AAA progression compared to men as reflected by enhanced aneurysm growth rates and a higher rupture risk. Women are diagnosed with AAA at an older age than men, and in line with increased osteoporosis and cardiovascular events, the delayed AAA onset has been attributed to the reduction of the protective effect of oestrogens during the menopausal transition. However, new insights have shown that a high follicle stimulating hormone (FSH) level during menopause may also play a key role in those diseases. In this report we hypothesize that FSH may aggravate AAA development and progression in postmenopausal women via a direct and/or indirect role, promoting aorta pathology. Since FSH receptors (FSHR) are reported on many other cell types than granulosa cells in the ovaries, it is feasible that FSH stimulation of FSHR-bearing cells such as aortic endothelial cells or inflammatory cells, could promote AAA formation directly. Indirectly, AAA progression may be influenced by an FSH-mediated increase in osteoporosis, which is associated with aortic calcification. Also, an FSH-mediated decrease in cholesterol uptake by the liver and an increase in cholesterol biosynthesis will increase the cholesterol level in the circulation, and subsequently promote aortic atherosclerosis and inflammation. Lastly, FSH-induced adipogenesis may lead to obesity-mediated dysfunction of the microvasculature of the aorta and/or modulation of the periaortic adipose tissue. Thus the long term increased plasma FSH levels during the menopausal transition may contribute to enhanced AAA disease in menopausal women and could be a potential novel target for treatment to lower AAA-related events in women.

scholarly journals The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective

Nanomaterials ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2991
Author(s):  
Lena M. Ernst ◽  
Eudald Casals ◽  
Paola Italiani ◽  
Diana Boraschi ◽  
Victor Puntes
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Inorganic Nanoparticles ◽  
Cellular Debris ◽  
Abnormal Cells ◽  
Nanoparticle Design ◽  
Modes Of Interaction ◽  
Molecular Patterns

The immune system contributes to maintaining the body’s functional integrity through its two main functions: recognizing and destroying foreign external agents (invading microorganisms) and identifying and eliminating senescent cells and damaged or abnormal endogenous entities (such as cellular debris or misfolded/degraded proteins). Accordingly, the immune system can detect molecular and cellular structures with a spatial resolution of a few nm, which allows for detecting molecular patterns expressed in a great variety of pathogens, including viral and bacterial proteins and bacterial nucleic acid sequences. Such patterns are also expressed in abnormal cells. In this context, it is expected that nanostructured materials in the size range of proteins, protein aggregates, and viruses with different molecular coatings can engage in a sophisticated interaction with the immune system. Nanoparticles can be recognized or passed undetected by the immune system. Once detected, they can be tolerated or induce defensive (inflammatory) or anti-inflammatory responses. This paper describes the different modes of interaction between nanoparticles, especially inorganic nanoparticles, and the immune system, especially the innate immune system. This perspective should help to propose a set of selection rules for nanosafety-by-design and medical nanoparticle design.

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