Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage

Anna Barkaway; Loïc Rolas; Régis Joulia; Jennifer Bodkin; Tchern Lenn; Charlotte Owen-Woods; Natalia Reglero-Real; Monja Stein; Laura Vázquez-Martínez; Tamara Girbl; Robin N Poston; Matthew Golding; Rebecca S Saleeb; Aude Thiriot; Ulrich H von Andrian; Johan Duchene; Mathieu-Benoit Voisin; Cleo L Bishop; David Voehringer; Axel Roers; Antal Rot; Tim Lämmermann; Sussan Nourshargh

doi:10.1016/j.immuni.2021.04.025

Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage

Immunity. 2021 Jul 13;54(7):1494-1510.e7. doi: 10.1016/j.immuni.2021.04.025. Epub 2021 May 24.

Authors

Anna Barkaway¹, Loïc Rolas¹, Régis Joulia¹, Jennifer Bodkin¹, Tchern Lenn¹, Charlotte Owen-Woods¹, Natalia Reglero-Real¹, Monja Stein¹, Laura Vázquez-Martínez¹, Tamara Girbl¹, Robin N Poston¹, Matthew Golding¹, Rebecca S Saleeb¹, Aude Thiriot², Ulrich H von Andrian², Johan Duchene³, Mathieu-Benoit Voisin¹, Cleo L Bishop⁴, David Voehringer⁵, Axel Roers⁶, Antal Rot⁷, Tim Lämmermann⁸, Sussan Nourshargh⁹

Affiliations

¹ Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
² Department of Immunology and HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, MA 02115, USA; The Ragon Institute of MGH, MIT and Harvard, Cambridge MA 02139, USA.
³ Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillians-Universität (LMU) München, Munich 80336, Germany.
⁴ Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
⁵ Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen 91054, Germany.
⁶ Institute for Immunology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden 01069, Germany.
⁷ Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Centre for Inflammation and Therapeutic Innovation, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
⁸ Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
⁹ Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Centre for Inflammation and Therapeutic Innovation, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: [email protected].

Abstract

Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.

Keywords: ACKR1; CXCR2; Neutrophils; aging; chemokines; diapedesis; endothelium; extravasation; inflammation; mast cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / immunology*
Animals
Biological Transport / immunology*
Chemokine CXCL1 / immunology
Endothelial Cells / immunology
Endothelium, Vascular / immunology
Female
Inflammation / immunology*
Intercellular Junctions / immunology
Lung / immunology
Male
Mice
Mice, Inbred C57BL
Neutrophils / immunology*
Receptors, Interleukin-8B / immunology
Venules / immunology

Substances

Chemokine CXCL1
Receptors, Interleukin-8B

Abstract

Publication types

MeSH terms

Substances

Grants and funding