Contribution of mast cells to injury mechanisms in a mouse model of pediatric traumatic brain injury.
The cognitive and behavioral deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than injuries to the adult brain. Understanding this developmental sensitivity is critical because children under 4 years of age of sustain TBI more frequently than any other age group. One of the first events after TBI is the infiltration and degranulation of mast cells (MCs) in the brain, releasing a range of immunomodulatory substances; inhibition of these cells is neuroprotective in other types of neonatal brain injury. This study investigates for the first time the role of MCs in mediating injury in a P7 mouse model of pediatric contusion-induced TBI. We show that various neural cell types express histamine receptors and that histamine exacerbates excitotoxic cell death in primary cultured neurons. Cromoglycate, an inhibitor of MC degranulation, altered the inflammatory phenotype of microglia activated by TBI, reversing several changes but accentuating others, when administered before TBI. However, without regard to the time of cromoglycate administration, inhibiting MC degranulation did not affect cell loss, as evaluated by ventricular dilatation or cleaved caspase-3 labeling, or the density of activated microglia, neurons, or myelin. In double-heterozygous cKit mutant mice lacking MCs, this overall lack of effect was confirmed. These results suggest that the role of MCs in this model of pediatric TBI is restricted to subtle effects and that they are unlikely to be viable neurotherapeutic targets. © 2016 Wiley Periodicals, Inc.
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.|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.
Donatella
D
Bettati
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|PremUP, Paris, France.|Università degli studi di Udine, Udine, Italy.
Elena
E
Banino
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|PremUP, Paris, France.|Università degli studi di Udine, Udine, Italy.
Silvana
S
De Lucia
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.
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.
Julien
J
Pansiot
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|PremUP, Paris, France.
Sowmyalakshmi
S
Rasika
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|PremUP, Paris, France.|Department of Anesthesia and Intensive Care, Pitié Salpétrière Hospital, Paris, France.
Vincent
V
Degos
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|PremUP, Paris, France.
Luigi
L
Titomanlio
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|PremUP, Paris, France.|Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom.
Pierre
P
Gressens
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France. bobbi.fleiss@inserm.fr.|PremUP, Paris, France. bobbi.fleiss@inserm.fr.|Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom. bobbi.fleiss@inserm.fr.
Bobbi
B
Fleiss
D000818:Animals; D000070624:Brain Contusion / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000473:pathology*; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002675:Child, Preschool; D004205:Cromolyn Sodium / Q000494:pharmacology; D004195:Disease Models, Animal; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007223:Infant; D008407:Mast Cells / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011968:Receptors, Histamine / Q000378:metabolism
D011968:Receptors, Histamine; D006632:Histamine; D019009:Proto-Oncogene Proteins c-kit; C505409:Casp3 protein, mouse; D053148:Caspase 3; D004205:Cromolyn Sodium
apoptosis; histamine; microglia; myelin; neuroinflammation; neuron