Maternal immune activation in late gestation increases neuroinflammation and aggravates experimental autoimmune encephalomyelitis in the offspring

Author(s)

Zager, Adriano ^[1] ; Peron, Jean Pierre ^[2] ; Mennecier, Gregory ^[1] ; Rodrigues, Sandra C. ^[3] ; Aloia, Thiago P. ^[1] ; Palermo-Neto, Joao ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Pathol, Sch Vet Med, Neuroimmunomodulat Res Grp, BR-05508270 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Neuroimmune Interact Lab, BR-05508270 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508270 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: BRAIN BEHAVIOR AND IMMUNITY; v. 43, p. 159-171, JAN 2015.
• Web of Science Citations: 19

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. 120 mu g/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 MOG(35-55). The EAE clinical symptoms were followed for 30 days. Different sets of animals were sacrificed either during the onset (7 days post-immunization {[}p.i.]), when spleen and lymph nodes were collected, or the peak of disease (20 days pi.), when CNS were collected for flow cytometry, cytokine production, and protein/mRNA-expression analysis. The primary CNS cultures from the LPS-reated group produced exaggerated amounts of IL-6, IL-1 beta 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. (C) 2014 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 09/51886-3 - Neuroimmunomodulation: drugs, stress and cytokines on nervous, endocrine and immune systems relationships
• Grantee: João Palermo Neto
• Support Opportunities: Research Projects - Thematic Grants