Microglia priming by interleukin-6 signaling is enhanced in aged mice

Katherine M. Garner, Ravi Amin, Rodney W. Johnson, Emily J. Scarlett, Michael D. Burton

Research output: Contribution to journalArticlepeer-review

Abstract

During peripheral infection, excessive production of pro-inflammatory cytokines in the aged brain from primed microglia induces exaggerated behavioral pathologies. While the pro-inflammatory cytokine IL-6 increases in the brain with age, its role in microglia priming is not known. This study examined the functional role of IL-6 signaling on microglia priming. Our hypothesis is that IL-6 signaling mediates primed states of microglia in the aged. An initial study assessed age-related alteration in IL-6 signaling molecules; sIL-6R and sgp130 were measured in cerebrospinal fluid of young and aged wild-type animals. Subsequent studies of isolated microglia from C57BL6/J (IL-6+/+) and IL-6 knock-out (IL-6−/−) mice showed significantly less MHC-II expression in aged IL-6−/− compared to IL-6+/+ counterparts. Additionally, adult and aged IL-6+/+ and IL-6−/− animals were administered lipopolysaccharide (LPS) to simulate a peripheral infection; sickness behaviors and hippocampal cytokine gene expression were measured over a 24 h period. Aged IL-6−/− animals were resilient to LPS-induced sickness behaviors and recovered more quickly than IL-6+/+ animals. The age-associated baseline increase of IL-1β gene expression was ablated in aged IL-6−/− mice, suggesting IL-6 is a key driver of cytokine activity from primed microglia in the aged brain. We employed in vitro studies to understand molecular mechanisms in priming factors. MHC-II and pro-inflammatory gene expression (IL-1β, IL-10, IL-6) were measured after treating BV.2 microglia with sIL-6R and IL-6 or IL-6 alone. sIL-6R enhanced expression of both pro-inflammatory genes and MHC-II. Taken together, these data suggest IL-6 expression throughout life is involved in microglia priming and increased amounts of IL-6 following peripheral LPS challenge are involved in exaggerated sickness behaviors in the aged.

Original languageEnglish (US)
Pages (from-to)90-99
Number of pages10
JournalJournal of Neuroimmunology
Volume324
DOIs
StatePublished - Nov 15 2018

Keywords

  • IL-6 trans signaling
  • Inflammation
  • MHC-II
  • Neuroimmunology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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