Sequential activation of microglia and astrocyte cytokine expression precedes alterations in immunoreactivity following systemic immune challenge
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Date
2016-05
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The Ohio State University
Abstract
Bi-directional communication between the periphery and the central nervous system (CNS) is essential for resolving infection. Within the CNS, microglia and astrocytes play a key role in initiating the neuroimmune response to peripheral infection by producing inflammatory signals that influence both brain and body. One issue in glial biology, however, is that glial morphological analysis alone is often used to measure the brain’s neuroinflammatory response to immune challenge. The purpose of this study, therefore, was to compare the behavioral sickness response following lipopolysaccharide (LPS) injection to the specific morphological and cytokine mRNA expression profiles of microglia and astrocytes. We report that LPS challenge induced a transient sickness response, characterized by decreased locomotion and social exploration, which was largely resolved by 48 h. The height of pro-inflammatory cytokine expression occurred between 2-12 hours in microglia and astrocytes, corresponding with active sickness. Despite the robust, rapid induction of pro-inflammatory cytokines by microglia between 2-4 h, the expression of cytokines and chemokines by astrocytes was delayed and peaked at 12 h. Notably, alterations in microglial morphology (Iba-1) were not observed until 24- 48 h after infection, while changes in astrocyte morphology (GFAP) were altogether absent. Additionally, repeated LPS injections did not elicit active sickness behavior or correlate with changes in glial morphology. Cytokine expression profiles following repeated LPS challenge indicated a weakened pro-inflammatory response and a shift toward immune tolerance. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge.
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Keywords
microglia, astrocytes, lipopolysaccharide, neuroinflammation, sickness behavior