Role of microglia in a mouse model of paediatric traumatic brain injury.
The cognitive and behavioural deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than TBI in the mature brain. Understanding this developmental sensitivity is critical as children under four years of age sustain TBI more frequently than any other age group. Microglia (MG), resident immune cells of the brain that mediate neuroinflammation, are activated following TBI in the immature brain. However, the type and temporal profile of this activation and the consequences of altering it are still largely unknown. In a mouse model of closed head weight drop paediatric brain trauma, we characterized i) the temporal course of total cortical neuroinflammation and the phenotype of ex vivo isolated CD11B-positive microglia/macrophage (MG/MΦ) using a battery of 32 markers, and ii) neuropathological outcome 1 and 5days post-injury. We also assessed the effects of targeting MG/MΦ activation directly, using minocycline a prototypical microglial activation antagonist, on these processes and outcome. TBI induced a moderate increase in both pro- and anti-inflammatory cytokines/chemokines in the ipsilateral hemisphere. Isolated cortical MG/MΦ expressed increased levels of markers of endogenous reparatory/regenerative and immunomodulatory phenotypes compared with shams. Blocking MG/MΦ activation with minocycline at the time of injury and 1 and 2days post-injury had only transient protective effects, reducing ventricular dilatation and cell death 1day post-injury but having no effect on injury severity at 5days. This study demonstrates that, unlike in adults, the role of MG/MΦ in injury mechanisms following TBI in the immature brain may not be negative. An improved understanding of MG/MΦ function in paediatric TBI could support translational efforts to design therapeutic interventions.
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France; Department of Anesthesia and Intensive Care, Georges Pompidou European Hospital, Paris, France.
Vibol
V
Chhor
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France; Università degli Studi di Udine, Udine, Italy.
Raffaella
R
Moretti
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Tifenn
T
Le Charpentier
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Stephanie
S
Sigaut
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Sophie
S
Lebon
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Leslie
L
Schwendimann
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Marie-Virginie
MV
Oré
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Chiara
C
Zuiani
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Valentina
V
Milan
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Julien
J
Josserand
Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom.
Regina
R
Vontell
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Julien
J
Pansiot
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France; Department of Anesthesia and Intensive Care, Pitié Salpétrière Hospital, F-75013 Paris, France.
Vincent
V
Degos
Department of Neurology, University of Wisconsin, Madison, WI, USA.
Chrysanthy
C
Ikonomidou
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France.
Luigi
L
Titomanlio
Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Clinical Sciences, Sahlgrenska Academy/East Hospital, Gothenburg University, 416 85 Gothenburg, Sweden.
Henrik
H
Hagberg
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France; Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom.
Pierre
P
Gressens
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; PremUP, Paris, France; Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom. Electronic address: Bobbi.Fleiss@inserm.fr.
Bobbi
B
Fleiss
D000818:Animals; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000276:immunology / Q000378:metabolism; D000070642:Brain Injuries, Traumatic / Q000276:immunology / Q000378:metabolism*; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology
D018925:Chemokines; D016207:Cytokines; D008911:Minocycline
Apoptosis; Cerebral; Chemokine; Cytokine; Immature; Inflammation; Macrophage; Minocycline; Neuron; Phenotype