Phosphatidyl-Inositol-3 Kinase Inhibitors Regulate Peptidoglycan-Induced Myeloid Leukocyte Recruitment, Inflammation, and Neurotoxicity in Mouse Brain.
Phosphatidyl-Inositol-3 Kinase Inhibitors Regulate Peptidoglycan-Induced Myeloid Leukocyte Recruitment, Inflammation, and Neurotoxicity in Mouse Brain.
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DOI：
10.3389/fimmu.2018.00770
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发表时间：
2018
影响因子：
7.3
通讯作者：
Iribarren P
中科院分区：
文献类型：
--
作者：
Arroyo DS;Gaviglio EA;Peralta Ramos JM;Bussi C;Avalos MP;Cancela LM;Iribarren P
急性脑损伤导致免疫细胞的募集和活化，包括驻留的小胶质细胞和浸润的外周髓样细胞（MC），其有助于参与神经元损伤的炎症反应。我们以前报道过，TLR 2刺激肽聚糖（PGN）从金黄色葡萄球菌，在体外和体内，诱导小胶质细胞活化，然后诱导自噬。在这篇报告中，我们评估了磷脂酰肌醇-3激酶（PI 3 K）药理学抑制剂LY 294200和3-甲基腺嘌呤（3-MA）是否可以调节中枢神经系统对PGN的先天性免疫反应。我们发现将PGN注射到小鼠脑实质（尾壳核）中引发炎症反应，其涉及小胶质细胞的活化、浸润MC向注射部位的募集、促炎介质的产生和神经元损伤。此外，我们观察到LC 3B + CD 45+细胞的积累以及LC 3B和溶酶体相关膜蛋白1在脑细胞中的共定位。此外，我们发现，PI 3 K的药理学抑制剂，包括经典的自噬抑制剂3-MA，减少了MC的募集，小胶质细胞的激活，以及脑PGN注射诱导的神经毒性。总的来说，我们的研究结果表明，PI 3 K通路和自噬反应可能参与PGN诱导的小胶质细胞活化和MC招募到大脑。因此，抑制这些途径可以作为治疗目标，以控制急性脑部炎症性疾病。
Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.
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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
影响因子：
16.8
作者：
Fukao, T;Koyasu, S
通讯作者：
Koyasu, S
影响因子：
4.8
作者：
Anand, Paras K.;Tait, Stephen W. G.;Kanneganti, Thirumala-Devi
通讯作者：
Kanneganti, Thirumala-Devi
影响因子：
4.4
作者：
Esen, Nilufer;Kielian, Tammy
通讯作者：
Kielian, Tammy
影响因子：
6.1
作者：
Carloni, Silvia;Buonocore, Giuseppe;Balduini, Walter
通讯作者：
Balduini, Walter