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Lomei, Jalal
Publications (7 of 7) Show all publications
Lomei, J. (2018). Characterization of pro-angiogenic neutrophils. Paper presented at 52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.. European Journal of Clinical Investigation, 48(S1), 81-81
Open this publication in new window or tab >>Characterization of pro-angiogenic neutrophils
2018 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 81-81Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366626 (URN)10.1111/eci.12926 (DOI)000434100200181 ()
Conference
52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.
Note

Meeting Abstract: P028-T

Available from: 2018-11-23 Created: 2018-11-23 Last updated: 2018-12-10Bibliographically approved
Lomei, J. (2018). Functional characterization of pro-angiogenic neutrophils. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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
Gabl, M., Holdfeldt, A., Sundqvist, M., Lomei, J., Dahlgren, C. & Forsman, H. (2017). FPR2 signaling without beta-arrestin recruitment alters the functional repertoire of neutrophils. Biochemical Pharmacology, 145, 114-122
Open this publication in new window or tab >>FPR2 signaling without beta-arrestin recruitment alters the functional repertoire of neutrophils
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2017 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 145, p. 114-122Article in journal (Refereed) Published
Abstract [en]

G-protein coupled receptor (GPCR) biased agonism or functional selectivity has become an essential concept in GPCR research over the last years. Receptor-specific biased agonists selectively trigger one signaling pathway over another and induce a restricted/directed functional response. In this study, we aimed to characterize the concept of biased agonism for FPR2, a member of the formyl peptide receptor (FPR) subfamily of GPCRs. We show that the earlier described FPR2-activating pepducin F2Pal(10) is a biased FPR2 agonist. The effects of F2Pal(10) on neutrophil function differed in several aspects compared to those mediated by WKYMVM, a conventional FPR2-specific peptide agonist. Upon interaction with FPR2 expressed by neutrophils both F2Pal(10) and WKYMVM activated the PLC-PIP2-Ca2+ signaling pathway and the superoxide-generating NADPH-oxidase, but only WKYMVM activated the receptor to recruit B-arrestin. The functional consequences linked to a lack of B-arrestin recruitment were further explored, and we demonstrate that FPR2 desensitization occurred independent of B-arrestin. Despite this, reactivation of desensitized receptors achieved through a disruption of the cytoskeleton and through a novel FPR2 cross-talk mechanism with P2Y(2)R (the ATP receptor) and PAFR (the receptor for PAF) differed between F2Pal(10)-desensitized and WKYMVM-desensitized neutrophils. Further, the inability to recruit beta-arrestin was found to be associated with a reduced rate of receptor internalization and impaired chemotaxis in neutrophils. In summary, we provide experimental evidence of biased agonism for FPR2 and our data disclose critical roles of beta-arrestin in neutrophil chemotaxis and reactivation of desensitized receptors. (C) 2017 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2017
Keywords
Formyl peptide receptor, Pepducin, beta-Arrestin, Chemotaxis, Biased agonism, Desensitization, Reactivation
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-342657 (URN)10.1016/j.bcp.2017.08.018 (DOI)000415784600012 ()28855087 (PubMedID)
Funder
Swedish Research Council, 2015-005601Swedish Research Council, 2015-02448Åke Wiberg Foundation, M15-0051
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28Bibliographically approved
Christoffersson, G., Lomei, J., O'Callaghan, P., Kreuger, J., Engblom, S. & Phillipson, M. (2017). Vascular sprouts induce local attraction of proangiogenic neutrophils. Journal of Leukocyte Biology, 102, 741-751
Open this publication in new window or tab >>Vascular sprouts induce local attraction of proangiogenic neutrophils
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2017 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, p. 741-751Article in journal (Refereed) Published
National Category
Physiology Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-196483 (URN)10.1189/jlb.1MA0117-018R (DOI)000413395700019 ()
Projects
eSSENCE
Available from: 2017-06-05 Created: 2013-03-10 Last updated: 2018-11-12Bibliographically approved
Massena, S., Christoffersson, G., Vågesjö, E., Seignez, C., Gustafsson, K., Binet, F., . . . Phillipson, M. (2015). Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood, 126(17), 2016-2026
Open this publication in new window or tab >>Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 17, p. 2016-2026Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-265201 (URN)10.1182/blood-2015-03-631572 (DOI)000366389200012 ()26286848 (PubMedID)
Funder
Swedish Research CouncilThe Royal Swedish Academy of SciencesMagnus Bergvall FoundationSwedish Diabetes AssociationÅke Wiberg FoundationRagnar Söderbergs stiftelseKnut and Alice Wallenberg Foundation
Available from: 2015-10-25 Created: 2015-10-25 Last updated: 2018-01-10Bibliographically approved
Lomei, J., Seignez, C., Giraud, A., Herrera Hidalgo, C., Shibuya, M., Christoffersson, G. & Phillipson, M.Characterization of pro-angiogenic neutrophils.
Open this publication in new window or tab >>Characterization of pro-angiogenic neutrophils
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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
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:nbn:se:uu:diva-362053 (URN)
Funder
Knut and Alice Wallenberg FoundationRagnar Söderbergs stiftelse
Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-12-04
Lomei, J., Christoffersson, G. & Phillipson, M.Pro-angiogenic neutrophils are potentiated by hypoxia.
Open this publication in new window or tab >>Pro-angiogenic neutrophils are potentiated by hypoxia
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Abstract

Hypoxia, shortage of oxygen in tissues, is closely related to injury, inflammation and tissue damage. One way to overcome this issue is increasing angiogenesis, growing new blood vessels from preexist-ing ones, at the site of hypoxia. Considerable number of cells, factors and signaling pathways are involved in regulating angiogenesis.

Neutrophils have been detected at the site of hypoxia and it has been shown that a subpopulation of these cells, pro-angiogenic neutrophils, PANs is actively involved in increasing angiogenesis. In this study, the effect of hypoxia on PANs was studied by co-culturing PANs with growing endothelial cells using in vitro angiogenesis assay and hypoxic and normoxic incubator. Moreover, life spans of neutrophils and PANs, as well as expression of PANs specific markers have been investigated under hypoxia and normoxia.  

Our data shows that the ability of PANs, to induce angiogenesis was increased under hypoxic conditions. Moreover larger number of PANs survived while co-culturing with active growing endothelial cells. We thereby conclude that the hypoxic microenvironment primes pro-angiogenic neutrophils increase their pro-angiogenic ability.

Keywords
Neutrophils, angiogenesi, hypoxia
National Category
Immunology in the medical area
Research subject
Immunology; Biology with specialization in Molecular Immunology
Identifiers
urn:nbn:se:uu:diva-362052 (URN)
Funder
Ragnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-10-03
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