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J Exp Med. 2014 Jun 30;211(7):1307-14. doi: 10.1084/jem.20132413. Epub 2014 Jun 9.

Neutrophils recruited by chemoattractants in vivo induce microvascular plasma protein leakage through secretion of TNF.

Author information

1
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, England, UK.
2
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, England, UK National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, England, UK.
3
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, England, UK s.nourshargh@qmul.ac.uk.

Abstract

Microvascular plasma protein leakage is an essential component of the inflammatory response and serves an important function in local host defense and tissue repair. Mediators such as histamine and bradykinin act directly on venules to increase the permeability of endothelial cell (EC) junctions. Neutrophil chemoattractants also induce leakage, a response that is dependent on neutrophil adhesion to ECs, but the underlying mechanism has proved elusive. Through application of confocal intravital microscopy to the mouse cremaster muscle, we show that neutrophils responding to chemoattractants release TNF when in close proximity of EC junctions. In vitro, neutrophils adherent to ICAM-1 or ICAM-2 rapidly released TNF in response to LTB4, C5a, and KC. Further, in TNFR(-/-) mice, neutrophils accumulated normally in response to chemoattractants administered to the cremaster muscle or dorsal skin, but neutrophil-dependent plasma protein leakage was abolished. Similar results were obtained in chimeric mice deficient in leukocyte TNF. A locally injected TNF blocking antibody was also able to inhibit neutrophil-dependent plasma leakage, but had no effect on the response induced by bradykinin. The results suggest that TNF mediates neutrophil-dependent microvascular leakage. This mechanism may contribute to the effects of TNF inhibitors in inflammatory diseases and indicates possible applications in life-threatening acute edema.

PMID:
24913232
PMCID:
PMC4076577
DOI:
10.1084/jem.20132413
[Indexed for MEDLINE]
Free PMC Article

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