Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage - IPBS-Toulouse, Hybrid Seminar (seminar room)

Dr. Loic Rolas

Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London UK

Ageing is the primary risk factor for inflammatory disorders but little is known about neutrophil-microvessel wall interactions in vivo. To address, neutrophil trafficking was analysed by confocal intravital microscopy in inflamed cremaster muscles of aged (>18months) and young (2-4months) mice. Surprisingly, in response to IL-1β, aged mice exhibited a high frequency of neutrophil reverse motility within endothelial cell (EC) junctions, with neutrophils that had initiated diapedesis reverse migrating back into the vascular lumen. This response, termed reverse transendothelial cell migration (rTEM), was absent in young mice. Mechanistically, rTEM in aged mice was driven by mast cells (MCs) as MC depletion or global MC deficiency abrogated neutrophil rTEM. At the molecular level, stimulated aged MCs released abnormally high levels of CXCL1 which was retained at EC junction by the atypical chemokine receptor ACKR1. This sequence of events caused CXCR2 desensitisation on neutrophils in close apposition to EC junctions, promoting rTEM.

In addressing the pathophysiological impact of neutrophil rTEM, fluorescent tracking revealed that in aged mice neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they exhibited an activated phenotype. Interestingly, i.v. injection of sorted rTEM neutrophils into naïve recipients indicated lung vascular leakage only in aged mice, demonstrating the importance of aged pulmonary vasculature in supporting the noxious phenotype of rTEM neutrophils. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.

Selected publications

• Barkaway A*, Rolas L* et al. Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage. Immunity. 2021 54(7):1494-1510.e7
• Reglero-Real N, Pérez-Gutiérrez L, Yoshimura A, Rolas L et al. Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation. Immunity. 2021 54(9):1989-2004.e9
• Rolas L et al. NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation. Gut. 2018 67(8):1505-1516
• Rolas L et al. Inhibition of mammalian target of rapamycin aggravates the respiratory burst defect of neutrophils from decompensated patients with cirrhosis. Hepatology. 2013 57(3):1163-71
• Boussif A, Rolas L et al. Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis. J Hepatol. 2016 64(5):1041-1048