Mast cell TLR2 signaling is crucial for effective killing of Francisella tularensis.
Mast cell TLR2 signaling is crucial for effective killing of Francisella tularensis.
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DOI：
10.4049/jimmunol.1200039
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发表时间：
2012-06-01
期刊：
影响因子：
--
通讯作者：
Arulanandam BP
中科院分区：
文献类型：
--
作者：
Rodriguez AR;Yu JJ;Guentzel MN;Navara CS;Klose KE;Forsthuber TG;Chambers JP;Berton MT;Arulanandam BP
toll样受体（TLR）信号传导对早期宿主防御病原体至关重要，但肥大细胞TLR介导的机制及其在肺部感染期间的后续效应功能的贡献在很大程度上是未知的。我们之前已经证明，肥大细胞通过产生IL-4，有效地控制土拉菌的复制。本研究利用高毒力的土拉菌SCHU S4和活疫苗菌株（LVS）来研究弗朗西斯菌肥大细胞tlr调控的贡献。肥大细胞需要TLR2来有效地杀死细菌，调节水解酶组织蛋白酶L，协调和运输MHCII和溶酶体相关膜蛋白2 （LAMP2）。与WT和TLR4−/−相比，受感染的TLR2−/−肥大细胞缺乏可检测到的IL-4，并且随着土拉菌复制增加2-3倍，细胞死亡增加，但可以通过重组IL-4处理获救。重要的是，与TLR2−/−小鼠相比，WT小鼠肺中标记土拉菌的MHCII和LAMP2定位更大。这些结果为肥大细胞和tlr2介导的信号在肺土拉菌感染后肺部早期先天过程中的重要效应贡献提供了证据，并为细胞内病原体调节呼吸道免疫防御的可能机制提供了额外的见解。
Toll-like receptor (TLR) signaling is critical for early host defense against pathogens, but the contribution of mast cell TLR-mediated mechanisms and subsequent effector functions during pulmonary infection is largely unknown. We have previously demonstrated that mast cells, through the production of IL-4, effectively control Francisella tularensis replication. In this study, the highly human virulent strain of F. tularensis SCHU S4 and the Live Vaccine Strain (LVS) were utilized to investigate the contribution of mast cell-TLR regulation of Francisella. Mast cells required TLR2 for effective bacterial killing, regulation of the hydrolytic enzyme cathepsin L, and for coordination and trafficking of MHCII and lysosomal associated membrane protein 2 (LAMP2). Infected TLR2−/− mast cells, in contrast to WT and TLR4−/−, lacked detectable IL-4 and displayed increased cell death with a 2–3 log increase of F. tularensis replication, but could be rescued with recombinant IL-4 treatment. Importantly, MHCII and LAMP2 localization with labeled F. tularensis in the lungs was greater in WT than in TLR2−/− mice. These results provide evidence for the important effector contribution of mast cells and TLR2-mediated signaling on early innate processes in the lung following pulmonary F. tularensis infection and provide additional insight into possible mechanisms by which intracellular pathogens modulate respiratory immune defenses.
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