title: Evidence for a gender-specific protective role of innate immune receptors in a model of perinatal brain injury.
abstract: Hypoxia-ischemia is a common cause of neurological impairments in newborns, but little is known about how neuroinflammation contributes to the long-term outcome after a perinatal brain injury. In this study, we investigated the role of the fractalkine receptor chemokine CX3C motif receptor 1 (CX3CR1) and of toll-like receptor (TLR) signaling after a neonatal hypoxic-ischemic brain injury. Mice deficient in the TLR adaptor proteins Toll/interleukin-1 receptor-domain-containing adaptor protein inducing interferon β (TRIF) or myeloid differentiation factor-88 (MyD88) and CX3CR1 knock-out (KO) mice were subjected to hypoxia-ischemia at postnatal day 3. In situ hybridization was used to evaluate the expression of TLRs during brain development and after hypoxic-ischemic insults. Behavioral deficits, hippocampal damage, reactive microgliosis, and subplate injury were compared among the groups. Although MyD88 KO mice exhibited no differences from wild-type animals in long-term structural and functional outcomes, TRIF KO mice presented a worse outcome, as evidenced by increased hippocampal CA3 atrophy in males and by the development of learning and motor deficits in females. CX3CR1-deficient female mice showed a marked increase in brain damage and long-lasting learning deficits, whereas CX3CR1 KO male animals did not exhibit more brain injury than wild-type mice. These data reveal a novel, gender-specific protective role of TRIF and CX3CR1 signaling in a mouse model of neonatal hypoxic-ischemic brain injury. These findings suggest that future studies seeking immunomodulatory therapies for preterm infants should consider gender as a critical variable and should be cautious not to abrogate the protective role of neuroinflammation.
authors.affiliation: Neuroscience Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Pimentel-Coelho
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Michaud
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D004195:Disease Models, Animal; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics; D012727:Sex Characteristics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000073883:CX3C Chemokine Receptor 1; D019707:Receptors, Chemokine; C471885:Cx3cr1 protein, mouse; C476286:Ticam1 protein, mouse