title: Perinatal Arterial Ischemic Stroke Is Associated to Materno-Fetal Immune Activation and Intracranial Arteritis.
abstract: The medium-size intra-cranial arteries arising from the carotid bifurcation are prone to perinatal arterial ischemic strokes (PAIS). PAIS' physiopathology needs to be better understood to develop preventive and therapeutic interventions that are currently missing. We hypothesized that materno-fetal inflammation leads to a vasculitis affecting selectively the carotidian tree and promoting a focal thrombosis and subsequent stroke. Dams were injected with saline or lipopolysaccharide (LPS) fromEscherichia coli. A prothrombotic stress was applied on LPS-exposed vs. saline (S)-exposed middle cerebral arteries (MCA). Immunolabeling detected the inflammatory markers of interest. In S-exposed newborn pups, a constitutive higher density of macrophages combined to higher expressions of tumor necrosis factor-α (TNF-α), and interleukin 1β (IL-1β) was observed within the wall of intra- vs. extra-cranial cervicocephalic arteries. LPS-induced maternal and placental inflammatory responses mediated by IL-1β, TNF-α and monocyte chemotactic protein 1 (MCP-1) were associated with: (i) increased density of pro-inflammatory macrophages (M1 phenotype); and (ii) pro-inflammatory orientation of the IL-1 system (IL-1β/IL-1 receptor antagonist (IL-1Ra) ratio) within the wall of LPS-, vs. S-exposed, intra-cranial arteries susceptible to PAIS. LPS plus photothrombosis, but not sole photothrombosis, triggered ischemic strokes and subsequent motor impairments. Based on these preclinical results, the combination of pro-thrombotic stress and selective intra-cranial arteritis arising from end gestational maternal immune activation seem to play a role in the pathophysiology of human PAIS.
authors.affiliation: Département de Pédiatrie, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. clemence.guiraut@usherbrooke.ca.
authors.forename: Clémence
authors.initials: C
authors.lastname: Guiraut
authors.affiliation: Département de Médecine Nucléaire et Radiobiologie, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. nicole.cauchon@usherbrooke.ca.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cauchon
authors.affiliation: Département de Médecine Nucléaire et Radiobiologie, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. martin.lepage@usherbrooke.ca.
authors.forename: Martin
authors.initials: M
authors.lastname: Lepage
authors.affiliation: Département de Pédiatrie, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. guillaume.sebire@mcgill.ca.|Child Neurology Division, Department of Pediatrics, McGill University, Montréal, QC H4A 3J1, Canada. guillaume.sebire@mcgill.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sébire
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001167:Arteritis / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014657:Vasculitis / Q000209:etiology / Q000276:immunology / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha
keywords: gestational inflammation; lipopolysaccharide; perinatal arterial ischemic stroke; vasculitis