Lipopolysaccharide-induced interleukin (IL)-4 receptor-α expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice.
Lipopolysaccharide-induced interleukin (IL)-4 receptor-α expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice.
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DOI：
10.1016/j.bbi.2011.10.003
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发表时间：
2012-07
影响因子：
15.1
通讯作者：
Godbout, Jonathan P.
中科院分区：
文献类型：
--
作者：
Fenn, Ashley M.;Henry, Christopher J.;Huang, Yan;Dugan, Allison;Godbout, Jonathan P.
在几种衰老模型中，小胶质细胞变得更具炎症性，对免疫挑战更具反应性。例如，外周LPS注射导致与老年BALB/c小鼠长期患病和抑郁样行为相关的过度小胶质细胞活化。因此，本研究的目的是确定年龄相关的扩增的小胶质细胞活化与抗炎和M2促进细胞因子白介素（IL）-10和IL-4的敏感性降低的程度。在对成年小鼠的初步研究中，LPS诱导小胶质细胞中M1和M2 mRNA谱的时间依赖性增加。此外，外周注射LPS显著增加小胶质细胞表面IL-4受体α（IL-4 R α）的表达，但不增加IL-10受体1（IL-10 R1）的表达。在BV-2细胞中，IL-4而不是IL-10将LPS激活的小胶质细胞重定向至M2表型。基于这些发现，在成年（3-4月龄）和老年（18-22月龄）小鼠的小胶质细胞中测定了M1和M2活化特征、IL-4 R α诱导和对IL-4的敏感性。在老年小胶质细胞，LPS促进了夸张和延长M1和M2的配置文件相比，成人。此外，LPS注射后，衰老小胶质细胞上的IL-4 R α蛋白没有增加。为了确定IL-4 R α上调受损的后果，向成年和老年小鼠注射LPS，然后分离活化的小胶质细胞并用IL-4离体处理。虽然离体IL-4诱导成年小鼠的活化小胶质细胞中的M2分布，但老年小鼠的活化小胶质细胞保留了突出的M1分布。这些数据表明，来自老年小鼠的活化小胶质细胞对IL-4的抗炎和M2促进作用不太敏感。
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-4Rα), 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-4Rα, 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-4Rα protein was not increased on aged microglia following LPS injection. To determine the consequence of impaired IL-4Rα 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.
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影响因子：
4.2
作者：
Bachstetter, Adam D.;Morganti, Josh M.;Jernberg, Jennifer;Schlunk, Andrea;Mitchell, Staten H.;Brewster, Kaelin W.;Hudson, Charles E.;Cole, Michael J.;Harrison, Jeffrey K.;Bickford, Paula C.;Gemma, Carmelina
通讯作者：
Gemma, Carmelina
脑膜免疫调节学习和记忆：IL-4 的关键作用。
影响因子：
15.3
作者：
Derecki, Noel C.;Cardani, Amber N.;Yang, Chun Hui;Quinnies, Kayla M.;Crihfield, Anastasia;Lynch, Kevin R.;Kipnis, Jonathan
通讯作者：
Kipnis, Jonathan
影响因子：
15.1
作者：
Chen, Jing;Buchanan, Jessica B.;Johnson, Rodney W.
通讯作者：
Johnson, Rodney W.
影响因子：
4.8
作者：
Clarke, Rachael M.;Lyons, Anthony;Lynch, Marina A.
通讯作者：
Lynch, Marina A.
影响因子：
3.3
作者：
Godbout, JP;Berg, GM;Johnson, RW
通讯作者：
Johnson, RW