Regulation of Central Nervous System Inflammation by Anti-inflammatory Cytokines in Activated Microglia and Impairments in Aging
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Date
2013-05
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The Ohio State University
Abstract
Prolonged central nervous system (CNS) inflammation is a problem because it can cause behavioral and neurological complications including depression and cognitive dysfunction. After a peripheral immune stimulus microglia, the innate immune cells of the CNS, become activated and release pro-inflammatory cytokines. Regulation of microglia by anti-inflammatory cytokines including interleukin (IL)-4, IL-10, and transforming growth factor beta (TGFβ) may be necessary to transition to a less inflammatory repair phenotype. In normal aging, however, this process may be impaired as microglia from aged animals have a prolonged and exaggerated inflammatory response and are resistant to anti-inflammatory feedback. This impairment of microglia regulation may explain the comorbidity of depression and cognitive problems with peripheral illnesses and injury in elderly people. To identify how these regulatory processes can become impaired with age, we first wanted to establish the extent to which activated microglia from adult mice are sensitive to IL-4, IL-10, and TGFβ. We report that activation of microglia in vivo with lipopolysaccharide (LPS), a component of gram negative bacteria cell wall, increased the expression of IL-4 receptor (IL-4Rα), but not IL-10 receptor (IL-10R1) on the surface of microglia. IL-4 and TGFβ decreased inflammatory cytokine expression and increased anti-inflammatory cytokine expression in vitro but IL-10 had no such effect. In adult ex vivo cultures, TGFβ decreased production of IL-1β and increased production of IL-4Rα; IL-4 treatment decreased inducible nitric oxide synthase (iNOS) and increased arginase expression. In aged ex vivo cultures, TGFβ had no significant effect on IL-1β, CX3CR1, and IL-4Rα expression; IL-4 treatment increased IL-1β, had no effect on iNOS, and increased arginase expression. Preliminary data from intracranioventricular (ICV) injection of a TGFβ inhibitor following intraperitoneal (i.p.) LPS injection show a significant lack of social exploratory behavior at 24 h
and a tendency towards higher expression of IL-1β and IL-6 from brain slice mRNA. Expression of IL-4Rα and IL-10R1 on microglia from LPS-injected adult BALB/c mice was determined by flow cytometry. BV2 cells, a mouse microglia cell line, were treated with IL-4, IL-10, or TGFβ in the presence or absence of LPS and mRNA levels were determined using qPCR. Primary microglia cultures established from neonatal mice were treated with TGFβ and LPS and mRNA was analyzed using qPCR. Ex vivo cultures were established from adult or aged BALB/c mice microglia that were LPS-activated in vivo; mRNA was analyzed using qPCR. These findings indicate that IL-4 and TGFβ are more potent anti-inflammatory mediators for microglia than IL-10. IL-4 and TGFβ treatment redirects activated microglia towards a less inflammatory phenotype. In aged microglia, however, there is an incomplete resolution of inflammation with IL-4 or TGFβ treatment.
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Keywords
microglia, neuroinflammation, aging