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

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

doi:10.1016/j.immuni.2021.04.025

Abstract

SummaryAging 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.

Highlights

Aging is a high-risk factor for the onset of inflammatory conditions, especially in life-threatening pulmonary and cardiovascular disorders (Akbar and Gilroy, 2020; Ferrucci and Fabbri, 2018; Nikolich-Zugich, 2018; Robba et al, 2020; Vabret et al, 2020)
Inflamed aged stroma promotes aberrant neutrophil transendothelial cell migration The impact of age on neutrophil-venular wall interactions was investigated in inflamed mouse cremaster muscles that due to its translucency is amenable to high resolution intravital microscopy (IVM)
Cremaster muscles were acutely inflamed via local injection of IL-1b in young and aged mice and leukocyte responses were investigated in real-time

Summary

Introduction

Aging is a high-risk factor for the onset of inflammatory conditions, especially in life-threatening pulmonary and cardiovascular disorders (Akbar and Gilroy, 2020; Ferrucci and Fabbri, 2018; Nikolich-Zugich, 2018; Robba et al, 2020; Vabret et al, 2020). Regardless of the primary insult being a pathogenic microbe or sterile injury, a significant cause of mortality and comorbidity in older patients is increased susceptibility to organ dysfunction remote from the initial inflammatory trigger. This is illustrated by the SARS-CoV-2 pandemic, as elderly patients with COVID-19 are at risk of pneumonia and present multiple organ failure (Akbar and Gilroy, 2020; Robba et al, 2020; Vabret et al, 2020). The underlying basis of this is complex and linked to multiple factors, such as compromised cell-intrinsic leukocyte

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