Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Psychology, University of Innsbruck, Innsbruck, Austria.
PLoS One. 2022 May 4;17(5):e0267860. doi: 10.1371/journal.pone.0267860. eCollection 2022.
Toll-like receptors (TLR) are one of the main constituents of the innate immune system in mammals. They can detect conserved microbial structures (pathogen-associated molecular patterns) and host-derived ligands that are produced during cellular stress and damage (danger-associated molecular patterns) and may then initiate an intracellular signaling cascade leading to the expression of pro-inflammatory cytokines and immediate immune responses. Some TLR (TLR1, 2, 4, 5, and 6) are expressed on the cell surface while others (TLR3, 7, 8 and 9) are present on the surface of endosomes and their ligands require internalization before recognition is possible. Several TLR have also been detected in neurons where they may serve functions that are not related to immune responses. TLR2, 3, and 4 have been described in cortical neurons and, for TLR4, a seizure-promoting role in epilepsies associated with inflammation has been shown. TLR3, 7, and 8 expressed in neurons seem to influence the growth or withdrawal of neurites and robust activation of TLR8 in neurons may even induce neuronal death. The goal of the current study was to investigate the expression of TLR8 in the hippocampus of mice during postnatal development and in adulthood. We focused on three functionally distinct groups of GABAergic interneurons characterized by the expression of the molecular markers parvalbumin, somatostatin, or calretinin, and we applied double fluorescence immunohistochemistry and cell counts to quantify co-expression of TLR8 in the three groups of GABA-interneurons across hippocampal subregions. We found subregion-specific differences in the expression of TLR8 in these interneurons. During postnatal development, TLR8 was detected only in mice older than P5. While only a small fraction of hippocampal calretinin-positive interneurons expressed TLR8, most parvalbumin-positive interneurons in all hippocampal subregions co-expressed TLR8. Somatostatin-positive interneurons co-expressing TLR8 were mainly present in hippocampal sector CA3 but rare in the dentate gyrus and CA1. High expression of TLR8 in parvalbumin-interneurons may contribute to their high vulnerability in human temporal lobe epilepsy.
Toll 样受体 (TLR) 是哺乳动物固有免疫系统的主要组成部分之一。它们可以检测到保守的微生物结构（病原体相关分子模式）和宿主在细胞应激和损伤过程中产生的配体（危险相关分子模式），然后启动细胞内信号级联反应，导致促炎细胞因子的表达和即时免疫反应。一些 TLR（TLR1、2、4、5 和 6）表达在细胞表面，而其他 TLR（TLR3、7、8 和 9）存在于内体表面，其配体需要内化后才能被识别。一些 TLR 也在神经元中被检测到，在神经元中，它们可能具有与免疫反应无关的功能。TLR2、3 和 4 已在皮质神经元中被描述，并且已经证明 TLR4 在与炎症相关的癫痫中具有促进癫痫发作的作用。在神经元中表达的 TLR3、7 和 8 似乎影响神经突的生长或缩回，并且 TLR8 在神经元中的强烈激活甚至可能诱导神经元死亡。本研究的目的是研究 TLR8 在小鼠出生后发育和成年期海马中的表达。我们专注于三种功能上不同的 GABA 能中间神经元群，其特征是表达分子标记物 parvalbumin、somatostatin 或 calretinin，我们应用双重荧光免疫组织化学和细胞计数来定量海马亚区中这三种 GABA 能中间神经元中 TLR8 的共表达。我们发现这些中间神经元在 TLR8 的表达上存在亚区特异性差异。在出生后发育过程中，TLR8 仅在大于 P5 的小鼠中被检测到。虽然只有一小部分海马 calretinin 阳性中间神经元表达 TLR8，但所有海马亚区的大多数 parvalbumin 阳性中间神经元都共表达 TLR8。共表达 TLR8 的 somatostatin 阳性中间神经元主要存在于海马扇区 CA3 中，但在齿状回和 CA1 中很少见。TLR8 在 parvalbumin 阳性中间神经元中的高表达可能导致它们在人类颞叶癫痫中的高易感性。
