Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection.
Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection.
复制标题
DOI：
10.1016/j.bbi.2017.05.020
复制
发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Kriz J
中科院分区：
文献类型：
--
作者：
Lalancette-Hébert M;Faustino J;Thammisetty SS;Chip S;Vexler ZS;Kriz J
小胶质细胞对脑损伤和/或免疫刺激的反应与Toll样受体(TLRs)的显著诱导有关。虽然在成人脑中，包括TLR2在内的单个TLRs在病理生理学级联中的作用已经得到很好的证实，但对它们在未成熟脑中的作用和时空诱导模式的了解还很少。为了验证感染性刺激和无菌炎症刺激是否会触发不同的TLR2介导的天然免疫反应，我们在出生后第9天(P9)小鼠中使用了三种模型，一种是全身注射内毒素诱导的感染模型，另一种是无菌炎症模型，分别是皮质内注射IL-1β和短暂性大脑中动脉阻塞(TMCAO)。我们利用在小鼠TLR2启动子转录控制下携带荧光素酶/GFP双重报告系统的转基因小鼠模型(TLR2-Luc-GFP)来观察活着的新生儿脑中TLR2的反应，然后测定神经炎症、小胶质细胞激活和白细胞浸润。结果表明，在生理性出生后脑发育中，TLR2-LUC信号在出生后第二周和第三周经历了显着的~30倍的下降和时空变化。我们随后发现，当内毒素在活体脑内强烈诱导TLR2-LUC信号并增加几种炎性细胞因子和趋化因子的水平时，IL-1β和tMCAO后体内TLR2-LUC信号减弱，炎症反应减弱。免疫荧光显示，在出生后大脑发育和所有三个研究的新生儿模型中，小胶质细胞是TLR2产生的主要来源。流式细胞术显示急性脑损伤后CD11b+/CD45+和CD11b+/Ly6C+细胞群发育变化，单核细胞系细胞受累，但缺乏Ly6G+中性粒细胞或CD3+细胞。总而言之，我们的结果表明，在PAMP和未成熟脑中由潮湿介导的炎症之后，TLR2的诱导模式截然不同。
Activation of microglial cells in response to brain injury and/or immune stimuli is associated with a marked induction of Toll-like receptors (TLRs). While in adult brain, the contribution of individual TLRs, including TLR2, in pathophysiological cascades has been well established, their role and spatial and temporal induction patterns in immature brain are far less understood. To examine whether infectious stimuli and sterile inflammatory stimuli trigger distinct TLR2-mediated innate immune responses, we used three models in postnatal day 9 (P9) mice, a model of infection induced by systemic endotoxin injection and two models of sterile inflammation, intra-cortical IL-1β injection and transient middle cerebral artery occlusion (tMCAO). We took advantage of a transgenic mouse model bearing the dual reporter system luciferase/GFP under transcriptional control of a murine TLR2 promoter (TLR2-luc-GFP) to visualize the TLR2 response in the living neonatal brain and then determined neuroinflammation, microglial activation and leukocyte infiltration. We show that in physiological postnatal brain development the in vivo TLR2-luc signal undergoes a marked ~30 fold decline and temporal-spatial changes during the second and third postnatal weeks. We then show that while endotoxin robustly induces the in vivo TLR2-luc signal in the living brain and increases levels of several inflammatory cytokines and chemokines, the in vivo TLR2-luc signal is reduced after both IL-1β and tMCAO and the inflammatory response is muted. Immunofluorescence revealed that microglial cells are the predominant source of TLR2 production during postnatal brain development and in all three neonatal models studied. Flow cytometry revealed developmental changes in CD11b+/CD45+ and CD11b+/Ly6C+ cell populations, involvement of cells of the monocyte lineage, but lack of Ly6G+ neutrophils or CD3+ cells in acutely injured neonatal brains. Cumulatively, our results suggest distinct TLR2 induction patterns following PAMP and DAMP - mediated inflammation in immature brain.
登录
查看更多内容
影响因子：
4.7
作者：
Andreasson KI;Bachstetter AD;Colonna M;Ginhoux F;Holmes C;Lamb B;Landreth G;Lee DC;Low D;Lynch MA;Monsonego A;O'Banion MK;Pekny M;Puschmann T;Russek-Blum N;Sandusky LA;Selenica ML;Takata K;Teeling J;Town T;Van Eldik LJ
通讯作者：
Van Eldik LJ
DOI：
10.1523/jneurosci.2102-11.2011
发表时间：
2011-09-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Faustino JV;Wang X;Johnson CE;Klibanov A;Derugin N;Wendland MF;Vexler ZS
通讯作者：
Vexler ZS
影响因子：
4.2
作者：
Allan, SM
通讯作者：
Allan, SM
影响因子：
4.8
作者：
Asea, A;Rehli, M;Calderwood, SK
通讯作者：
Calderwood, SK
DOI：
10.1161/atvbaha.110.210427
发表时间：
2010-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Abe Y;Kawakami A;Osaka M;Uematsu S;Akira S;Shimokado K;Sacks FM;Yoshida M
通讯作者：
Yoshida M