Hernandez Antonio, Bohannon Julia K, Luan Liming, Fensterheim Benjamin A, Guo Yin, Patil Naeem K, McAdams Chase, Wang Jingbin, Sherwood Edward R
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee;
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
J Leukoc Biol. 2016 Dec;100(6):1311-1322. doi: 10.1189/jlb.1A0216-072R. Epub 2016 Jun 27.
Treatment with the TLR4 agonist MPLA augments innate resistance to common bacterial pathogens. However, the cellular and molecular mechanisms by which MPLA augments innate immunocyte functions are not well characterized. This study examined the importance of MyD88- and TRIF-dependent signaling for leukocyte mobilization, recruitment, and activation following administration of MPLA. MPLA potently induced MyD88- and TRIF-dependent signaling. A single injection of MPLA caused rapid mobilization and recruitment of neutrophils, a response that was largely mediated by the chemokines CXCL1 and -2 and the hemopoietic factor G-CSF. Rapid neutrophil recruitment and chemokine production were regulated by both pathways although the MyD88-dependent pathway showed some predominance. In further studies, multiple injections of MPLA potently induced mobilization and recruitment of neutrophils and monocytes. Neutrophil recruitment after multiple injections of MPLA was reliant on MyD88-dependent signaling, but effective monocyte recruitment required activation of both pathways. MPLA treatment induced expansion of myeloid progenitors in bone marrow and upregulation of CD11b and shedding of L-selectin by neutrophils, all of which were attenuated in MyD88- and TRIF-deficient mice. These results show that MPLA-induced neutrophil and monocyte recruitment, expansion of bone marrow progenitors and augmentation of neutrophil adhesion molecule expression are regulated by both the MyD88- and TRIF-dependent pathways.
用Toll样受体4（TLR4）激动剂单磷酰脂质A（MPLA）进行治疗可增强对常见细菌病原体的天然抵抗力。然而，MPLA增强天然免疫细胞功能的细胞和分子机制尚未得到充分表征。本研究检测了髓样分化因子88（MyD88）依赖和TIR结构域衔接蛋白诱导干扰素β（TRIF）依赖的信号传导在MPLA给药后白细胞动员、募集和激活中的重要性。MPLA能有效诱导MyD88依赖和TRIF依赖的信号传导。单次注射MPLA可导致中性粒细胞迅速动员和募集，这一反应主要由趋化因子CXC趋化因子配体1（CXCL1）和CXCL2以及造血因子粒细胞集落刺激因子（G-CSF）介导。尽管MyD88依赖的途径显示出一定优势，但两条途径均调节中性粒细胞的快速募集和趋化因子产生。在进一步的研究中，多次注射MPLA能有效诱导中性粒细胞和单核细胞的动员和募集。多次注射MPLA后中性粒细胞的募集依赖于MyD88依赖的信号传导，但有效的单核细胞募集需要两条途径的激活。MPLA治疗可诱导骨髓中髓系祖细胞扩增，中性粒细胞表面CD11b上调以及淋巴细胞归巢受体L-选择素脱落，所有这些在MyD88和TRIF缺陷小鼠中均减弱。这些结果表明，MPLA诱导的中性粒细胞和单核细胞募集、骨髓祖细胞扩增以及中性粒细胞黏附分子表达增强均由MyD88依赖和TRIF依赖的途径调节。
