Lipopolysaccharide-induced interleukin (IL)-4 receptor-伪 expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice

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• 作者：Ashley M. Fenn^a ; Christopher J. Henry^a ; Yan Huang^a ; ^b ; Allison Dugan^b ; Jonathan P. Godbout^a ; ^b ; ^c ; ^{jonathan.godbout@osumc.edu}
• 关键词：Microglia ; Aging ; IL-4 ; IL-10 ; M1 and M2 activation profiles
• 刊名：Brain ; Behavior ; and Immunity
• 出版年：2012
• 期刊代码：79_08891591
• 类别：psy
• 出版时间：July, 2012
• 卷：26
• 期：5
• 页码：766-777
• 文件大小：824 K

摘要

In several models of aging, microglia become more inflammatory and reactive to immune challenges. For example, peripheral LPS injection causes exaggerated microglial activation associated with prolonged sickness and depressive-like behavior in aged BALB/c mice. Therefore, the purpose of this study was to determine the extent to which age-related amplified microglial activation was associated with reduced sensitivity to the anti-inflammatory and M2 promoting cytokines interleukin (IL)-10 and IL-4. In initial studies with adult mice, LPS induced a time-dependent increase in M1 and M2 mRNA profiles in microglia. Furthermore, peripheral LPS injection markedly increased surface expression of IL-4 receptor-alpha (IL-4R伪), but not IL-10 receptor-1 (IL-10R1) on microglia. In BV-2 cells, IL-4, but not IL-10, re-directed LPS-activated microglia towards an M2 phenotype. Based on these findings, comparisons of M1 and M2 activation profiles, induction of IL-4R伪, and sensitivity to IL-4 were determined in microglia from adult (3-4 mo) and aged (18-22 mo) mice. In aged microglia, LPS promoted an exaggerated and prolonged M1 and M2 profile compared to adults. Moreover, IL-4R伪 protein was not increased on aged microglia following LPS injection. To determine the consequence of impaired IL-4R伪 upregulation, adult and aged mice were injected with LPS and activated microglia were then isolated and treated ex vivo with IL-4. While ex vivo IL-4 induced an M2 profile in activated microglia from adult mice, activated microglia from aged mice retained a prominent M1 profile. These data indicate that activated microglia from aged mice are less sensitive to the anti-inflammatory and M2-promoting effects of IL-4.