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Resolvin D1 Triggered GPR32 Signaling in Human Macrophages

English title Resolvin D1 Triggered GPR32 Signaling in Human Macrophages
Applicant Hersberger Martin
Number 173088
Funding scheme Project funding (Div. I-III)
Research institution Abteilung für Klinische Chemie und Biochemie Kinderspital Universitäts-Kinderkliniken Zürich
Institution of higher education University of Zurich - ZH
Main discipline Cardiovascular Research
Start/End 01.11.2017 - 31.10.2021
Approved amount 570'556.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Cellular Biology, Cytology

Keywords (7)

GPCR signaling; Adipose tissue inflammation ; Resolution of inflammation; GPR32; Coronary artery disease; Resolvin D1; Phosphoproteome

Lay Summary (German)

Lead
Mit der Nahrung aufgenommene Omega-3 Fettsäuren sind essentiell für den menschlichen Körper und spielen bei Entzündungsreaktionen eine Rolle. Dabei werden die Omega-3 Fettsäuren zu Lipidmediatoren verstoffwechselt, die über spezifische Rezeptoren auf unser Immunsystem einwirken. Einer der entzündungshemmenden Lipidmediatoren ist Resolvin D1, der seine Wirkung über den Rezeptor GPR32 entfaltet.
Lay summary

Inhalt und Ziele des Forschungsprojekts

In diesem Projekt wollen wir die entzündungshemmende Wirkung des Lipidmediators Resolvin D1 auf das menschliche Immunsystem untersuchen und die menschlichen Zellen identifizieren, die durch Resolvin D1 beeinflusst werden. In diesen Zellen wollen wir die molekulare Signalkaskade beschreiben, die durch Resolvin D1 ausgelöst wird.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Verstehen der durch Resolvin D1 ausgelösten molekularen Vorgänge in menschlichen Zellen, die zu einer Entzündungshemmung führen, könnte uns neue Interventionsmöglichkeiten für die Medikamentenentwicklung aufzeigen. Solch neue Medikamentenklassen hätten das Potential bei verschiedenen chronisch entzündlichen Krankheiten eingesetzt zu werden.

 

Direct link to Lay Summary Last update: 18.09.2017

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
125142 The role of the second 15-lipoxygenase, ALOX15B, on atherosclerosis: the genetic approach 01.09.2009 Project funding (Div. I-III)
112472 The anti-inflammatory role of the 12-lipoxygenase and the lipoxin receptor ALXR in atherosclerosis: the genetic approach 01.06.2006 Project funding (Div. I-III)
125142 The role of the second 15-lipoxygenase, ALOX15B, on atherosclerosis: the genetic approach 01.09.2009 Project funding (Div. I-III)

Abstract

Background: Obesity leads to chronic inflammation of the adipose tissue, which is associated with the metabolic syndrome, type 2 diabetes and cardiovascular disease. Inflammation of the adipose tissue is mainly characterized by the presence of crown like structures composed of inflammatory macrophages in the neighbourhood of adipocytes. The lipoxygenase pathways play a role in leukocyte activation by the generation of two classes of arachidonic acid lipid mediators, the leukotrienes and the lipoxins and three classes of omega-3 fatty acid metabolites, the resolvins, the protectins, and the maresins. The leukotrienes have pro-inflammatory properties, while the lipoxins, resolvins and protectins appear at the time of resolution of inflammation and have anti-inflammatory properties. Resolvin D1 (RvD1) showed potent anti-inflammatory and pro-resolving effects in several mouse models of inflammation. In addition, RvD1 was recently measured in human plasma and adipose tissue following supplementation with omega-3 fatty acids and delivery of RvD1 to human adipose tissue explants reduced inflammation. However, the mechanism of these anti-inflammatory and pro-resolving effects in human adipose tissue and the intracellular signaling of RvD1 have not been elucidated.Own Work: to evaluate the mechanism of RvD1 mediated inhibition of adipose tissue inflammation, we have investigated the effect of RvD1 on primary human macrophages. We show that RvD1 reduces the secretion of the pro-inflammatory cytokines IL-1ß and IL-8, abolishes chemotaxis to several chemoattractants, and enhances the phagocytic activity of macrophages towards microbial particles, hence, polarizing macrophages towards an M2 like phenotype. In addition, we show that these RvD1 effects are mediated by triggering GPR32. In contrast, we show that RvD1 has no effect on human adipocytes.Working Hypothesis: We hypothesize that the anti-inflammatory and pro-resolving lipid mediator RvD1 reduces human adipose tissue inflammation through GPR32 triggered polarization of macrophages towards a M2 like phenotype, which in turn modulate the inflammatory tone of adipocytes. In addition, we hypothesize that RvD1 triggered GPR32 signaling involves rapid regulation of kinases and phosphatases blocking chemotaxis and enhancing phagocytosis of macrophages.Specific Aims: Specific aim 1: To investigate the effect of primary human macrophages stimulated with RvD1 on human adipocytes in a co-culture system, A)Transwell co-culture system, B) Overlay co-culture system. Specific aim 2: To investigate RvD1 triggered GPR32 signaling in human macrophages, A) Signal transduction to suppress chemotaxis induced by chemerin, fMLF, and MCP-1, B) Signal transduction to increase phagocytosis.Significance and Perspective: The lipid mediator RvD1 has anti-inflammatory and pro-resolving properties and the stable forms of this mediator may have the potential to serve as a novel class of anti-inflammatory drugs. The usefulness of this novel class of drugs, however, will depend on the expression of the RvD1 receptors GPR32 and FPR2/ALX on cells present in the inflamed tissue in humans, and on the role of RvD1 triggering in these cells. In addition, identifying the intracellular signaling pathways triggered by RvD1 may identify novel drug targets to improve efferocytosis and to reduce inflammation, both mechanisms implicated in atherosclerosis. In this context it is essential to perform these studies in primary human cells because there is no mouse orthologue for GPR32.
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