Biology subjects

Ibing, W.

Publications and source records attributed to Ibing, W..

3 recordsLinked to original sources

bioRxiv2025

Olfactory receptor 2 drives abdominal aortic aneurysm by promoting CX3CR1-mediated monocyte recruitment

BackgroundAbdominal aortic aneurysms (AAA) are characterized by an intricate interplay of extracellular matrix degradation and inflammation. Macrophages are centrally involved in these processes. The mechanisms underlying macrophage activation in AAA remain incompletely understood. Vascular macrophages have been shown to express olfactory receptor 2 (Olfr2), a G-protein coupled receptor involved in mediating the sense of smelling and regulating inflammatory activity in macrophages. Whether Olfr2 plays a role in modulating macrophage responses in AAA formation remains unknown. Methods & ResultsIn silico micro-array analysis showed increased expression of the human Olfr2 orthologue OR6A2 in AAA tissue compared to healthy aorta. Flow cytometric analysis revealed increased expression of OR6A2 on classical, non-classical, and intermediate monocytes of patients with a large AAA (> 5cm) in comparison to patients with smaller AAA (< 5cm). Up to 30% of vascular macrophages expressed OR6A2 in human AAA and Olfr2 in mouse AAA tissue. Olfr2 expression peaked on major histocompatibility complex II-high (MHCIIhigh) and C-C chemokine receptor type 2-low (CCR2low) aortic monocytes and macrophages on day 7 following experimental AAA initiation and decreased to baseline expression on day 28. Olfr2 gene (Olfr2-/-) deficiency protected mice from AAA formation, which was accompanied by lowered ECM degradation, reduced macrophage infiltration and increased smooth muscle cell content. Conversely, treatment with the Olfr2 agonist octanal exacerbated AAA formation and inflammation, while the antagonist citral reduced AAA formation in comparison to vehicle treated mice. Bulk transcriptome analysis of aortic tissue revealed reduced inflammatory gene expression in Olfr2-/- mice at day 7 following AAA initiation. Spectral flow cytometry resolved 20 aortic immune cell populations, which were largely reduced in quantity by Olfr2-deficiency at day 7 and day 28 post experimental AAA formation, while circulating leukocyte counts and monocyte subset distribution were not altered between Olfr2+/+ and Olfr2-/- mice. Circulating Ly6Chigh-monocytes exhibited reduced expression of the CX3C motif chemokine receptor 1 (CX3CR1) and CCR2 during AAA formation. Transcriptional analysis of monocytes confirmed downregulation of pathways associated with cell adhesion, motility and migration. In vitro, Olfr2-/- monocytes showed impaired migration towards the CX3CR1 ligand CX3CL1. Competitive transfer of Olfr2+/+ and Olfr2-/- monocytes confirmed reduced migratory capacity of Olfr2-/- monocytes into the developing AAA. ConclusionWe demonstrate a critical relevance for Olfr2 in the modulation of the inflammatory response underlying AAA, which is mediated by enhanced monocyte recruitment.

immunology↗

bioRxiv2023

Collagen receptor GPVI-mediated platelet activation and pro-coagulant activity aggravates inflammation and aortic wall remodelling in abdominal aortic aneurysm

Platelets play an important role in cardio- and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerotic-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall accompanied by chronic inflammation. Platelet activation and pro-coagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and men. The present study investigated the impact of the major platelet collagen receptor glycoprotein (GP)VI in cellular processes underlying AAA initiation and progression. Genetic deletion of GPVI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GPVI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Further, remodelling of the aortic wall was improved in absence of GPVI, indicated by reduced MMP2/9 and OPN plasma levels and an enhanced -SMA content within the aortic wall, accompanied by reduced cell apoptosis. As a result, an elevation in intima/media thickness and elastin content were observed in GPVI-deficient PPE mice, coursing a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In AAA patients, enhanced plasma levels of soluble GPVI and fibrin, besides fibrin accumulation within the intraluminal thrombus (ILT) suggested that GPVI might serve as a biomarker and mediator in fibrin-supported stabilization of the ILT. In conclusion, our results emphasize the potential need for a GPVI-targeted anti-platelet therapy to reduce AAA initiation and progression, as well as to protect AAA patients from aortic rupture. Translational perspectiveAbdominal aortic aneurysm (AAA) is an atherosclerotic-related, cardiovascular disease (CVD) with high mortality. The impact of platelets in different cellular processes underlying AAA initiation and progression remains unclear.Therefore, we analysed the role of the major platelet collagen receptor GPVI in the pathogenesis of AAA. Results from platelet depleted mice and patients with AAA revealed a significant contribution of GPVI to the inflammatory response and remodelling process of the aorta. Further, elevated accumulation of fibrin, a recently identified ligand of GPVI in the intraluminal thrombus (ILT) and in the plasma of AAA patients, suggests that GPVI binding to fibrin plays a role in ILT formation and probably stabilization of the abdominal aorta. Furthermore, increased levels of sGPVI suggest that GPVI might serve as a clinical biomarker for AAA. Thus, therapeutic targeting of GPVI-mediated platelet activation might be an effective anti-thrombotic strategy for AAA patients.

cell biology↗

bioRxiv2022

Platelets modulate inflammation and matrix remodeling in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases but their role in AAA is poorly understood. The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the ECM. They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodeling but also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity results in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity was also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodeling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall. In conclusion, our data strongly supports the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients. Translational perspectiveAbdominal aortic aneurysm (AAA) is a severe cardiovascular disease (CVD) with high mortality. Since the role of platelets is unclear, we explored platelet-mediated processes in the pathogenesis of AAA. Results from platelet depleted mice and patients with AAA revealed that platelets modulate inflammatory and stiffness-related gene expression of macrophages and fibroblasts. Further, platelets induce the release of osteopontin important for the recruitment of platelets to the aortic wall and to the intraluminal thrombus (ILT). Consequently, platelet depletion significantly reduced aneurysm growth. Thus, therapeutic targeting of platelet activation might be crucial for the treatment of patients to reduce AAA formation and progression.

molecular biology↗