Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes

Thomson, C., McColl, A., Graham, G. and Cavanagh, J. (2020) Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes. Journal of Neuroinflammation, 17, 94. (doi: 10.1186/s12974-020-01759-8) (PMID:32213184) (PMCID:PMC7098135)

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Abstract

Background: Recent years have seen an explosion of research pertaining to biological psychiatry, yet despite subsequent advances in our understanding of neuroimmune communication pathways, how the brain senses and responds to peripheral inflammation remains poorly understood. A better understanding of these pathways may be important for generating novel therapeutics to treat many patients with chronic inflammatory diseases who also suffer from neuropsychiatric comorbidities. Here we have systematically assessed the leukocyte infiltrate to the brain following systemic endotoxin exposure to better understand this novel route of neuroimmune communication. Methods: Mice were injected intraperitoneally with LPS daily for 2, 5 or 7 consecutive days. We systematically interrogated the subsequent induction of chemokine transcription in the brain using TaqMan low-density arrays. A combination of flow cytometry and immunohistochemistry was then used to characterise the accompanying leukocyte infiltrate Result: Repeated LPS challenges resulted in prolonged activation of brain-resident microglia, coupled with an increased local transcription of numerous chemokines. After 2 days of administering LPS, there was a marked increase in the expression of the neutrophil chemoattractants CXCL1 and CXCL2; the monocyte chemoattractants CCL2, CCL5, CCL7 and CCL8; and the lymphocyte chemoattractants CXCL9, CXCL10 and CXCL16. In a number of cases, this response was sustained for several days. Chemokine induction was associated with a transient recruitment of neutrophils and monocytes to the brain, coupled with a sustained accumulation of macrophages, CD8+ T cells, NK cells and NKT cells. Strikingly, neutrophils, monocytes and T cells appeared to extravasate from the vasculature and/or CSF to infiltrate the brain parenchyma. Conclusions: Prolonged exposure to a peripheral inflammatory stimulus triggers the recruitment of myeloid cells and lymphocytes to the brain. By altering the inflammatory or metabolic milieu of the brain, this novel method of immune-to-brain communication may have profound implications for patients with chronic inflammatory diseases, potentially leading to neuropsychiatric comorbidities.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Thomson, Miss Carolyn and Cavanagh, Professor Jonathan and McColl, Dr Alison and Graham, Professor Gerard
Authors: Thomson, C., McColl, A., Graham, G., and Cavanagh, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Neuroinflammation
Publisher:BioMed Central
ISSN:1742-2094
ISSN (Online):1742-2094
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Journal of Neuroinflammation 17:94
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171627The ACKR2-CCR2 axis in development and diseaseGerard GrahamMedical Research Council (MRC)MR/M019764/1III - Immunology
167227Dissecting the chemokine basis for the orchestration of the in vivo inflammatory responseGerard GrahamWellcome Trust (WELLCOTR)099251/Z/12/ZIII - Immunology