Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis

Jamie D Kraft; Robert Blomgran; Ida Bergström; Matúš Soták; Madison Clark; Alankrita Rani; Meenu Rohini Rajan; Jesmond Dalli; Sofia Nyström; Marianne Quiding-Järbrink; Jonathan Bromberg; Per Skoog; Emma Börgeson

doi:10.1096/fj.202101219RR

Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis

FASEB J. 2022 Mar;36(3):e22173. doi: 10.1096/fj.202101219RR.

Authors

Jamie D Kraft^{1

2}, Robert Blomgran³, Ida Bergström^{4

5}, Matúš Soták^{1

2

6}, Madison Clark^{1

2}, Alankrita Rani^{1

2

6}, Meenu Rohini Rajan^{1

2

6}, Jesmond Dalli^{7

8}, Sofia Nyström^{4

5}, Marianne Quiding-Järbrink⁹, Jonathan Bromberg^{10

11

12

13}, Per Skoog^{14

15}, Emma Börgeson^{1

2

6}

Affiliations

¹ Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
³ Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
⁴ Department of Clinical Immunology and Transfusion Medicine, Linköping University, Linköping, Sweden.
⁵ Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁶ Department of Clinical Physiology, Region Vaestra Goetaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁷ William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
⁸ Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK.
⁹ Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
¹¹ Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
¹² Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA.
¹³ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland, USA.
¹⁴ Department of Vascular Surgery and Institute of Medicine, Sahlgrenska University Hospital and Academy, Gothenburg, Sweden.
¹⁵ Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital and Academy, Gothenburg, Sweden.

Abstract

Dysregulated chronic inflammation plays a crucial role in the pathophysiology of atherosclerosis and may be a result of impaired resolution. Thus, restoring levels of specialized pro-resolving mediators (SPMs) to promote the resolution of inflammation has been proposed as a therapeutic strategy for patients with atherosclerosis, in addition to standard clinical care. Herein, we evaluated the effects of the SPM lipids, lipoxin A₄ (LXA₄ ) and lipoxin B₄ (LXB₄ ), on neutrophils isolated from patients with atherosclerosis compared with healthy controls. Patients displayed altered endogenous SPM production, and we demonstrated that lipoxin treatment in whole blood from atherosclerosis patients attenuates neutrophil oxidative burst, a key contributor to atherosclerotic development. We found the opposite effect in neutrophils from healthy controls, indicating a potential mechanism whereby lipoxins aid the endogenous neutrophil function in health but reduce its excessive activation in disease. We also demonstrated that lipoxins attenuated upregulation of the high-affinity conformation of the CD11b/CD18 integrin, which plays a central role in clot activation and atherosclerosis. Finally, LXB₄ enhanced lymphatic transmigration of human neutrophils isolated from patients with atherosclerosis. This finding is noteworthy, as impaired lymphatic function is now recognized as an important contributor to atherosclerosis. Although both lipoxins modulated neutrophil function, LXB₄ displayed more potent effects than LXA₄ in humans. This study highlights the therapeutic potential of lipoxins in atherosclerotic disease and demonstrates that the effect of these SPMs may be specifically tailored to the need of the individual.

Keywords: CD11b/CD18 integrin; atherosclerosis; cardiovascular disease; lipoxins; lymphatics transmigration; neutrophils; reactive oxygen species; resolution of inflammation; specialized pro-resolving mediators.

Publication types

Clinical Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Atherosclerosis / metabolism*
Female
Humans
Inflammation / metabolism
Integrins / metabolism*
Lipoxins / metabolism*
Male
Middle Aged
Neutrophils / metabolism*
Respiratory Burst / physiology*

Substances

Integrins
Lipoxins

Grants and funding

R37 AI062765/AI/NIAID NIH HHS/United States