Acute peripheral immune activation alters cytokine expression and glial activation in the early postnatal rat brain

Abstract

BackgroundNeuroinflammation can modulate brain development; however, the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized. To address this gap in knowledge, we evaluated the peripheral and central nervous system (CNS) immune responses to a mixed immune challenge in early postnatal rats of varying strains and sex.MethodsOn postnatal day 10 (P10), male and female Lewis and Brown Norway rats were injected intramuscularly with either a mix of bacterial and viral components in adjuvant, adjuvant-only, or saline. Immune responses were evaluated at 2 and 5 days post-challenge. Cytokine and chemokine levels were evaluated in serum and in multiple brain regions using a Luminex multiplex assay. Multi-factor ANOVAs were used to compare analyte levels across treatment groups within strain, sex, and day of sample collection. Numbers and activation status of astrocytes and microglia were also analyzed in the cortex and hippocampus by quantifying immunoreactivity for GFAP, IBA-1, and CD68 in fixed brain slices. Immunohistochemical data were analyzed using a mixed-model regression analysis.ResultsAcute peripheral immune challenge differentially altered cytokine and chemokine levels in the serum versus the brain. Within the brain, the cytokine and chemokine response varied between strains, sexes, and days post-challenge. Main findings included differences in T helper (Th) type cytokine responses in various brain regions, particularly the cortex, with respect to IL-4, IL-10, and IL-17 levels. Additionally, peripheral immune challenge altered GFAP and IBA-1 immunoreactivity in the brain in a strain- and sex-dependent manner.ConclusionsThese findings indicate that genetic background and sex influence the CNS response to an acute peripheral immune challenge during early postnatal development. Additionally, these data reinforce that the developmental time point during which the challenge occurs has a distinct effect on the activation of CNS-resident cells.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1569-2) contains supplementary material, which is available to authorized users.

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The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…There is increasing evidence that the aging immune system is skewed towards a more inflammatory status, increasing the probability and intensity of neuroinflammation [ 47 , 48 , 49 ]. In addition, a strong systemic inflammatory immune response may influence the brain function and cause corresponding syndromes and disease, as well as induce or aggravate neuroinflammation [ 50 , 51 , 52 ].…”

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“…21,22,[24][25][26] The propensity to develop neuroinflammation in association with peripheral immune activation is influenced by genetic background, sex, and postnatal age. 27 In humans, antecedents of perinatal brain injury and resultant neurodevelopmental impairments that might be mediated by systemic inflammation include maternal factors, such as socioeconomic status (SES) indicators, 28 pre-pregnancy obesity, 29,30 and FGR; 31 perinatal infections, such as sepsis; 32 tissue damage, as can occur with NEC 33 and ventilator-induced lung injury; 34 and preand postnatal exposure to environmental chemicals, as well as treatments given to neonates as a component of neonatal intensive care. 28,34,35 The heightened inflammatory response to LPS in male neonates, as compared to females, might contribute to males' higher risk of neurodevelopmental impairments.…”

“… 21 , 22 , 24 – 26 The propensity to develop neuroinflammation in association with peripheral immune activation is influenced by genetic background, sex, and postnatal age. 27 …”