3. Novel mouse models for the investigation of neuronal–glial immune interactions

Abstract

Immune challenge alters central nervous system (CNS)-mediated processes and complex behaviors. Pro-inflammatory cytokines such as interleukin-1 beta (IL-1) and tumor necrosis factor alpha (TNF) are well characterized immunomodulators that mediate multiple aspects of the innate immune response. IL-1 and TNF respectively bind to IL-1 receptor 1 (IL-1R1) and TNF p55 receptor (TNFR1) present on neurons and glia. Systemic or central administration of IL-1 or TNF elicits sickness behaviors including sleep–wake behavior alterations, decreased appetite, and social withdrawal. Furthermore, neurons and glia produce cytokines in response to an immune challenge. Collectively, these observations suggest neuronal–glial interactions involving cytokines are crucial to the manifestation of sickness behavior. Nevertheless, the relative contribution of neurons and glia to the modulation of complex behavior and physiology during immune challenge is not known. To address this knowledge gap, we engineered four transgenic mouse lines that express IL-1R1 or TNFR1 only in the CNS and selectively on neurons or astrocytes. These transgenic mice express either IL-1R1 or TNFR1 cDNA under transcriptional control of neuron-specific enolase or human glial fibrillary acidic protein promoters. Our animals provide a unique tool to study CNS responses to immune challenge independent from peripheral actions of IL-1 or TNF. The systematic and selective examination of neuronal–glial cytokine interactions will further our understanding of the central response to immune activation relevant to a spectrum of pathologies characterized by inflammation.