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

• Published in: Journal of neuroimmunology Vol. 324; pp. 90 - 99
• Main Authors: Garner, Katherine M., Amin, Ravi, Johnson, Rodney W., Scarlett, Emily J., Burton, Michael D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.11.2018
• Subjects: Aging - drug effects; Aging - immunology; Aging - metabolism; Animals; Cell Line; IL-6 trans signaling; Inflammation; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Interleukin-6 - immunology; Lipopolysaccharides - toxicity; Male; MHC-II; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - drug effects; Microglia - immunology; Microglia - metabolism; Neuroimmunology; Signal Transduction - physiology; STAT3; Inflammation; IL-6; LPS; sgp130; IL-6 trans signaling; TNF-α; sIL-6R; gp130; Neuroimmunology; IL-1B; CD68; CD45; MHC-II
• ISSN: 0165-5728; 1872-8421; 1872-8421
• DOI: 10.1016/j.jneuroim.2018.09.002

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. [Display omitted] •IL-6 trans-signaling is involved in microglia priming.•Microglia in aged mice are more susceptible to IL-6-induced priming.•Ablation of IL-6 signaling significantly reduces exaggerated LPS-induced sickness behaviors in aged animals.