Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity

Stephen, J., Scales, H.E. , Benson, R.A., Erben, D., Garside, P. and Brewer, J.M. (2017) Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity. npj Vaccines, 2, 1. (doi:10.1038/s41541-016-0001-5) (PMID:29263862) (PMCID:PMC5604741)

Stephen, J., Scales, H.E. , Benson, R.A., Erben, D., Garside, P. and Brewer, J.M. (2017) Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity. npj Vaccines, 2, 1. (doi:10.1038/s41541-016-0001-5) (PMID:29263862) (PMCID:PMC5604741)

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Abstract

There are over 6 billion vaccine doses administered each year, most containing aluminium-based adjuvants, yet we still do not have a complete understanding of their mechanisms of action. Recent evidence has identified host DNA and downstream sensing as playing a significant role in aluminium adjuvant (aluminium hydroxide) activity. However, the cellular source of this DNA, how it is sensed by the immune system and the consequences of this for vaccination remains unclear. Here we show that the very early injection site reaction is characterised by inflammatory chemokine production and neutrophil recruitment. Intravital imaging demonstrates that the Alum injection site is a focus of neutrophil swarms and extracellular DNA strands. These strands were confirmed as neutrophil extracellular traps due to their sensitivity to DNAse and absence in mice deficient in peptidylarginine deiminase 4. Further studies in PAD4−/− mice confirmed a significant role for neutrophil extracellular trap formation in the adjuvant activity of Alum. By revealing neutrophils recruited to the site of Alum injection as a source of the DNA that is detected by the immune system this study provides the missing link between Alum injection and the activation of DNA sensors that enhance adjuvant activity, elucidating a key mechanism of action for this important vaccine component.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Brewer, Professor James and Garside, Professor Paul and Stephen, Dr Jillian and Erben, Mr Dan and Benson, Dr Robert and Scales, Dr Hannah
Authors: Stephen, J., Scales, H.E., Benson, R.A., Erben, D., Garside, P., and Brewer, J.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:npj Vaccines
Publisher:Nature Publishing Group
ISSN:2059-0105
ISSN (Online):2059-0105
Published Online:23 January 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in npj Vaccines 2:1
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
534671Understanding and manipulating chemokines and their receptors in the context of adjuvantsJames BrewerBiotechnology and Biological Sciences Research Council (BBSRC)BB/I007768/1III -IMMUNOLOGY