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.
Highlights
Neuroinflammation can modulate brain development; the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized
Materials The mixed acute peripheral immune challenge was comprised of hepatitis B (HepB) (Recombivax HB; Merck & Co., Whitehouse Station, New Jersey), diphtheria and tetanus toxoids and acellular pertussis (DTap) (DAPTACEL; Sanofi Pasteur, Swiftwater, Pennsylvania), Haemophilus influenza type b (Hib) (PedvaxHIB; Merck & Co., Inc., Whitehouse Station, New Jersey), pneumococcal conjugate (PCV) (Prevnar 13; Wyeth Pharmaceuticals Inc., Madison, New Jersey), and inactivated poliovirus (IPV) (IPOL; Sanofi Pasteur, Swiftwater, Pennsylvania) in adjuvant
Sex- and region-specific differences in central nervous system (CNS) cytokine expression at baseline Immune signaling is important for early development, and sex-specific differences have been evidenced in peripheral and CNS immune signaling under normal conditions [20]
Summary
Neuroinflammation can modulate brain development; the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized. Immune signaling within the CNS is coordinated primarily by resident cells such as microglia, astrocytes, and mast cells due to tightly regulated infiltration of peripheral leukocytes into the brain parenchyma [9, 10] When activated, these resident immune cells secrete a range of cytokines, chemokines, and other regulatory factors that drive neuroinflammatory responses and contribute to normal neurodevelopment and functional homeostasis [11, 12]. Integration of systemic immune signals by CNS-resident cells may occur via coordinated signaling through the autonomic nervous system and the hypothalamicpituitary-adrenal (HPA) axis [13], trafficking and effector functions of immune cells within the meninges [14], and gut microbe-mediated mechanisms [15] Each of these systems undergoes overlapping periods of development and refinement during the first few weeks following birth. Immune activation during these critical periods of development can have broad implications on neurodevelopment and neural function later in life
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