title: Maternal immune activation in late gestation increases neuroinflammation and aggravates experimental autoimmune encephalomyelitis in the offspring.
abstract: Multiple sclerosis (MS) is characterized by an autoimmune response against myelin antigens driven by autoreactive T cells. Several lines of evidence indicate that environmental factors, such as previous infection, can influence and trigger autoimmune responses. However, the importance of the gestational period, particularly under inflammatory conditions, on the modulation of MS and related neuroinflammation by the offspring is unknown. This study aimed to evaluate the impact of prenatal exposure to lipopolysaccharide (LPS) during late gestation on the neuroinflammatory response in primary mixed glial cultures and on the progression of experimental autoimmune encephalomyelitis (EAE, an animal model of MS) in the offspring. LPS (Escherichia coli 0127:B8, 120μg/kg) was administered intraperitoneally to pregnant C57BL/6J mice on gestational day 17, and the offspring were assigned to two experiments: (1) mixed glial cultures generated using the brain of neonates, stimulated in vitro with LPS, and (2) adult offspring immunized with MOG35-55. The EAE clinical symptoms were followed for 30days. Different sets of animals were sacrificed either during the onset (7days post-immunization [p.i.]), when spleen and lymph nodes were collected, or the peak of disease (20days p.i.), when CNS were collected for flow cytometry, cytokine production, and protein/mRNA-expression analysis. The primary CNS cultures from the LPS-treated group produced exaggerated amounts of IL-6, IL-1β and nitrites after in vitro stimulus, while IL-10 production was lowered compared to the data of the control group. Prenatal exposure to LPS worsened EAE disease severity in adult offspring, and this worsening was linked to increased CNS-infiltrating macrophages, Th1 cells and Th17 cells at the peak of EAE severity; additionally, exacerbated gliosis was evidenced in microglia (MHC II) and astrocytes (GFAP protein level and immunoreactivity). The IL-2, IL-6 and IL-17 levels in the spleen and lymph nodes were increased in the offspring of the LPS-exposed dams. Our results indicate that maternal immune activation during late gestation predispose the offspring to increased neuroinflammation and potentiate the autoimmune response and clinical manifestation of EAE.
authors.affiliation: Neuroimmunomodulation Research Group, Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil. Electronic address: adrianozager@hotmail.com.
authors.forename: Adriano
authors.initials: A
authors.lastname: Zager
authors.affiliation: Neuroimmune Interactions Laboratory, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Peron
authors.affiliation: Neuroimmunomodulation Research Group, Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: Gregory
authors.initials: G
authors.lastname: Mennecier
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Rodrigues
authors.affiliation: Neuroimmunomodulation Research Group, Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: Thiago P
authors.initials: TP
authors.lastname: Aloia
authors.affiliation: Neuroimmunomodulation Research Group, Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: João
authors.initials: J
authors.lastname: Palermo-Neto
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D009043:Motor Activity / Q000276:immunology; D011247:Pregnancy
chemical_list: D016207:Cytokines
keywords: EAE; Macrophages; Maternal immune activation; Microglia; Mixed glial culture; Neuroinflammation; Prenatal LPS; T cells