title: Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury.
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.
authors.affiliation: Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK adelhelmy@cantab.net.
authors.forename: Adel
authors.initials: A
authors.lastname: Helmy
authors.affiliation: Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Mathew R
authors.initials: MR
authors.lastname: Guilfoyle
authors.affiliation: Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Keri L H
authors.initials: KLH
authors.lastname: Carpenter
authors.affiliation: Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Pickard
authors.affiliation: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: David K
authors.initials: DK
authors.lastname: Menon
authors.affiliation: Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hutchinson
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000627:therapeutic use*; D016018:Least-Squares Analysis; D008297:Male; D017551:Microdialysis; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors; D015599:Trauma Severity Indices; D055815:Young Adult
chemical_list: D018925:Chemokines; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins
keywords: Chemokines; brain trauma; inflammation; microglia; neurochemistry