Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury.


Type
Article
Change log
Authors
Guilfoyle, Mathew R 
Carpenter, Keri LH 
Pickard, John D 
Menon, David K 
Abstract

Interleukin-1 receptor antagonist (IL1ra) has demonstrated efficacy in a wide range of animal models of neuronal injury. We have previously published a randomised controlled study of IL1ra in human severe TBI, with concomitant microdialysis and plasma sampling of 42 cytokines and chemokines. In this study, we have used partial least squares discriminant analysis to model the effects of drug administration and time following injury on the cytokine milieu within the injured brain. We demonstrate that treatment with rhIL1ra causes a brain-specific modification of the cytokine and chemokine response to injury, particularly in samples from the first 48 h following injury. The magnitude of this response is dependent on the concentration of IL1ra achieved in the brain extracellular space. Chemokines related to recruitment of macrophages from the plasma compartment (MCP-1) and biasing towards a M1 microglial phenotype (GM-CSF, IL1) are increased in patient samples in the rhIL1ra-treated patients. In control patients, cytokines and chemokines biased to a M2 microglia phenotype (IL4, IL10, MDC) are relatively increased. This pattern of response suggests that a simple classification of IL1ra as an 'anti-inflammatory' cytokine may not be appropriate and highlights the importance of the microglial response to injury.

Description
Keywords
Chemokines, brain trauma, inflammation, microglia, neurochemistry, Adolescent, Adult, Brain, Brain Injuries, Traumatic, Chemokines, Cytokines, Female, Humans, Interleukin 1 Receptor Antagonist Protein, Least-Squares Analysis, Male, Microdialysis, Microglia, Middle Aged, Receptors, Interleukin-1, Recombinant Proteins, Time Factors, Trauma Severity Indices, Young Adult
Journal Title
J Cereb Blood Flow Metab
Conference Name
Journal ISSN
0271-678X
1559-7016
Volume Title
36
Publisher
SAGE Publications
Sponsorship
Medical Research Council (G0601025)
Medical Research Council (G9439390)
Medical Research Council (G0600986)
Medical Research Council (G1002277)
Medical Research Council (G0001354)
Medical Research Council (G0802251)
TCC (None)
Medical Research Council (G1000183)
AH is supported by a joint Medical Research Council/ Royal College of Surgeons of England Clinical Research Training Fellowship (G0802251). AH and MRG are supported by Raymond and Beverly Sackler Fellowships. MRG is supported by the Royal College of Surgeons of England Research Fellowship. KLHC is supported by the National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). DKM and JDP are supported by National Institute for Health Research Senior Investigator Awards. PJAH is supported by the Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship, the National Institute for Health Research Brain Repair Centre Collaborative and the National Institute for Health Research Research Professorship. Study Support was provided by the Medical Research Council (Grant number G0600986 ID 79068) and the National Institute for Health Research Brain Repair Centre Collaborative.