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Characterization of pro-angiogenic neutrophils
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Mia Phillipson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. (Mia Phillipson)ORCID iD: 0000-0002-6381-2968
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Mia Phillipson)ORCID iD: 0000-0002-8559-5781
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The roles of neutrophils in immune defense have been investigated for decades. These cells are well equipped to protect the body in several ways against invaders such as microorganism. Recently it has been reported that neutrophils also contribute to angiogenesis; they are recruited to the site of hypoxia where they can promote blood vessel formation, as demonstrated both in vivo and in vitro. We found that these neutrophils with proangiogenic actions form a specific subset of the circulating neutrophils. The proangiogenic neutrophils (PANs) exclusively express the adhesion molecule CD49d and vascular endothelial growth factor receptor 1 (VEGFR1), and contribute to angiogenesis by delivering MMP-9 (matrix metalloproteinase 9). In this study, PANs were compared to classic neutrophils in respect to physical features as well as functionality. We found that PANs in humans were smaller and in human and mice PANs had higher granularity compared to the classic neutrophils. Moreover, they were more efficient phagocytes than classic neutrophils. In the aortic ring model of angiogenesis, vessel neo-formation was increased by the presence of pro-angiogenic neutrophils. Finally, by using neutrophils from mice with impaired VEGFR1 receptor (Flt-1 tk-/- mice) we demonstrated the role of VEGFR1 in neutrophil recruitment towards angiogenic endothelium. Together these results show clear differences between the pro-angiogenic subpopulation and the classic neutrophils, which further solidify the conclusion of a specific neutrophil subpopulation.

Keywords [en]
Leukocytes, angiogenesis, phagocytosis, pro angiogenic neutrophils, ROS production
National Category
Immunology in the medical area
Research subject
Immunology; Biology with specialization in Molecular Immunology
Identifiers
URN: urn:nbn:se:uu:diva-362053OAI: oai:DiVA.org:uu-362053DiVA, id: diva2:1252598
Funder
Knut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseAvailable from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-12-04
In thesis
1. Functional characterization of pro-angiogenic neutrophils
Open this publication in new window or tab >>Functional characterization of pro-angiogenic neutrophils
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The vascular system stretches throughout the body to provide oxygen, nutrition, and to remove waste products from cell metabolism. Angiogenesis, formation of new blood vessels by sprouting from pre-existing vessels, is one of the main mechanisms involved in blood vessel formation. A successful angiogenic process is dependent on the timely involvement of several parameters; from different cell types to anti- and pro-angiogenic soluble factors.

White blood cells are mostly famous for being involved in host defense against pathogens, through rapid reactions by innate immunity and delayed but specific responses through adaptive immunity. The neutrophils are innate immune cells, which are the most abundant white blood cells in the circulation. In addition to their classical roles in defense against invading microorganisms, it was recently revealed that neutrophils actively contribute to angiogenesis. Neutrophils that are involved in angiogenesis comprise a specific population, namely pro-angiogenic neutrophils (PANs), that are recruited to sites of hypoxia by using different adhesion molecules compared to when they chemotax towards infection.

The present investigations focus on characterization of PANs and comparing them to the classic neutrophil population in terms of their physical features and their functions. By modifying and applying new in vivo and in vitro models of angiogenesis, interactions between growing endothelial cells and neutrophils have been further revealed, as well as neutrophil recruitment and movement towards an active site of angiogenesis. We found that the main neutrophil contribution to angiogenesis at site of islet transplantation occurs at early stages of revascularization to establish new vessels, where after the neutrophils leave the site. Neutrophil recruitment to a site of infection relies to a large extent on macrophage signals, but this was not the case when they were recruited to sites of hypoxia. PANs are a specific sub-population of neutrophils that significantly differ from the rest of the neutrophil population not only in terms of their active contribution to angiogenesis, but also in terms of their physical features and their phagocytosis abilities. The role of vascular endothelial growth factor receptor (VEGFR1) and also chemokine CXCL12 (CXCR4/CXCL12 signaling) in neutrophil recruitment has been further revealed by our in vitro model; neutrophil migration to sprouting endothelium is directed by CXCL12 and VEGFR1. Furthermore we found that hypoxic condition boosted pro-angiogenic activities of PANs. Moreover, how vascular permeability affects neutrophil recruitment was studied; vascular permeability regulates inflammation by increasing chemokine transport into the blood vessels and thereby promotes neutrophil recruitment.

In conclusion, functional characterization of pro-angiogenic neutrophils performed in this thesis demonstrates differences beyond marker expression when compared to classic neutrophils. Moreover, intricate interactions necessary for the formation of new blood vessels between neutrophils and the growing vasculature were shown. Increased understanding of the contribution of neutrophils to blood vessel formation in hypoxic environment or/and tumors could be exploited further to develop potential therapies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 58
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1498
Keywords
angiogenesis, leukocytes, neutrophils, pro-angiogenic neutrophils, islets transplantation, intravital microscopy, aortic ring assay, phagocytosis, ROS production, hypoxia, vascular permeability, neutrophil recruitment
National Category
Immunology in the medical area
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-362217 (URN)978-91-513-0457-1 (ISBN)
Public defence
2018-11-20, A1:107A, BMC, Husargatan 3, Uppsala, 09:30 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelse
Available from: 2018-10-30 Created: 2018-10-03 Last updated: 2018-11-26

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Lomei, JalalSeignez, CedricGiraud, AntoineHerrera Hidalgo, CarmenChristoffersson, GustafPhillipson, Mia

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Lomei, JalalSeignez, CedricGiraud, AntoineHerrera Hidalgo, CarmenChristoffersson, GustafPhillipson, Mia
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Department of Medical Cell BiologyIntegrative PhysiologyDepartment of Medical Biochemistry and Microbiology
Immunology in the medical area

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