Laflamme N, Soucy G, Rivest S
Laboratory of Molecular Endocrinology, CHUL Research Center and Department of Anatomy and Physiology, Laval University, Québec, Canada.
J Neurochem. 2001 Nov;79(3):648-57. doi: 10.1046/j.1471-4159.2001.00603.x.
The recent characterization of human homologs of Toll may be the missing link for the transduction events leading to nuclear factor-kappaB (NF-kappaB) activity and proinflammatory gene transcription during innate immune response. Mammalian cells may express as many as 10 distinct Toll-like receptors (TLRs), although TLR2 is a key receptor for recognizing cell wall components of Gram-positive bacteria. The present study investigated the effects of circulating bacterial cell wall components on the expression of the gene-encoding TLR2 across the mouse brain. Surprisingly, while Gram-negative components caused a robust increase in TLR2 transcription within the cerebral tissue, peptidoglycan (PGN) and lipoteichoic acid (LTA), either alone or combined, failed to modulate the receptor transcript. Indeed, the mRNA levels for TLR2 in the choroid plexus and few other regions of the brain remained similar between vehicle-, LTA-, PGN-, and LTA/PGN-administered mice at all the times evaluated (i.e. 30 min to 24 h post-intraperitoneal injection). This contrasts with the profound de novo expression of TLR2 following a single systemic injection of the lipopolysaccharide (LPS). The signal was first detected in regions devoid of blood-brain barrier and few blood vessels and microcapillaries. A second wave of TLR2 expression was also detected from these structures to their surrounding parenchymal cells that stained for a microglial marker iba1. The rapid induction of IkappaBalpha (index of NF-kappaB activity) and up-regulation of the adaptor protein MyD88 suggest that LPS-induced TLR2 transcription may be dependent on the NF-kappaB pathway. These data provide the evidence that TLR2 is not only present in the brain, but its encoding gene is regulated by cell wall components derived from Gram-negative, not Gram-positive, bacteria. The robust wave of TLR2-expressing microglial cells may have a determinant impact on the innate immune response that occurs in the brain during systemic infection by Gram-negative, not Gram-positive, bacteria.
Toll蛋白人类同源物的最新特性，可能是天然免疫反应过程中导致核因子-κB（NF-κB）活性及促炎基因转录的转导事件中缺失的环节。哺乳动物细胞可能表达多达10种不同的Toll样受体（TLR），尽管TLR2是识别革兰氏阳性菌细胞壁成分的关键受体。本研究调查了循环中的细菌细胞壁成分对小鼠全脑编码TLR2基因表达的影响。令人惊讶的是，虽然革兰氏阴性菌成分可使脑组织内TLR2转录显著增加，但单独或联合使用的肽聚糖（PGN）和脂磷壁酸（LTA）却无法调节该受体转录本。实际上，在所有评估时间点（即腹腔注射后30分钟至24小时），给予赋形剂、LTA、PGN和LTA/PGN的小鼠脉络丛及脑的其他少数区域中，TLR2的mRNA水平保持相似。这与单次全身注射脂多糖（LPS）后TLR2的大量从头表达形成对比。该信号首先在无血脑屏障以及血管和微毛细血管较少的区域被检测到。还从这些结构检测到第二波TLR2表达，其表达至周围对小胶质细胞标志物iba1染色的实质细胞。IkappaBalpha（NF-κB活性指标）的快速诱导及衔接蛋白MyD88的上调表明，LPS诱导的TLR2转录可能依赖于NF-κB途径。这些数据证明，TLR2不仅存在于脑中，而且其编码基因受革兰氏阴性菌而非革兰氏阳性菌来源的细胞壁成分调控。表达TLR2的小胶质细胞的大量涌现，可能对革兰氏阴性菌而非革兰氏阳性菌全身感染期间脑中发生的天然免疫反应具有决定性影响。
