Toll-like receptor 7 (TLR7) is an innate immune receptor that detects viral single-stranded RNA and triggers the production of proinflammatory cytokines and type 1 interferons in immune cells. TLR7 agonists also modulate sensory nerve function by increasing neuronal excitability, although studies are conflicting whether sensory neurons specifically express TLR7. This uncertainty has confounded the development of a mechanistic understanding of TLR7 function in nervous tissues. TLR7 expression was tested using in situ hybridization with species-specific RNA probes in vagal and dorsal root sensory ganglia in wild-type and TLR7 knockout (KO) mice and in guinea pigs. Since TLR7 KO mice were generated by inserting an Escherichia coli lacZ gene in exon 3 of the mouse TLR7 gene, wild-type and TLR7 (KO) mouse vagal ganglia were also labeled for lacZ. In situ labeling was compared to immunohistochemistry using TLR7 antibody probes. The effects of influenza A infection on TLR7 expression in sensory ganglia and in the spleen were also assessed. In situ probes detected TLR7 in the spleen and in small support cells adjacent to sensory neurons in the dorsal root and vagal ganglia in wild-type mice and guinea pigs, but not in TLR7 KO mice. TLR7 was co-expressed with the macrophage marker Iba1 and the satellite glial cell marker GFAP, but not with the neuronal marker PGP9.5, indicating that TLR7 is not expressed by sensory nerves in either vagal or dorsal root ganglia in mice or guinea pigs. In contrast, TLR7 antibodies labeled small- and medium-sized neurons in wild-type and TLR7 KO mice in a TLR7-independent manner. Influenza A infection caused significant weight loss and upregulation of TLR7 in the spleens, but not in vagal ganglia, in mice. TLR7 is expressed by macrophages and satellite glial cells, but not neurons in sensory ganglia suggesting TLR7’s neuromodulatory effects are mediated indirectly via activation of neuronally-associated support cells, not through activation of neurons directly. Our data also suggest TLR7’s primary role in neuronal tissues is not related to antiviral immunity.

中文翻译：

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TLR7 由神经节中的支持细胞表达，但不是感觉神经元

Toll 样受体 7 (TLR7) 是一种先天免疫受体，可检测病毒单链 RNA 并触发免疫细胞中促炎细胞因子和 1 型干扰素的产生。TLR7 激动剂还通过增加神经元的兴奋性来调节感觉神经功能，尽管关于感觉神经元是否特异性表达 TLR7 的研究存在争议。这种不确定性混淆了对神经组织中 TLR7 功能的机械理解的发展。在野生型和 TLR7 敲除 (KO) 小鼠和豚鼠中，使用与物种特异性 RNA 探针在迷走神经和背根感觉神经节中的原位杂交测试 TLR7 表达。由于 TLR7 KO 小鼠是通过在小鼠 TLR7 基因的外显子 3 中插入​​大肠杆菌 lacZ 基因产生的，因此野生型和 TLR7 (KO) 小鼠迷走神经节也被标记为 lacZ。将原位标记与使用 TLR7 抗体探针的免疫组织化学进行比较。还评估了甲型流感感染对感觉神经节和脾脏中 TLR7 表达的影响。原位探针在野生型小鼠和豚鼠的脾脏和与背根和迷走神经节感觉神经元相邻的小支持细胞中检测到 TLR7，但在 TLR7 KO 小鼠中未检测到。TLR7 与巨噬细胞标志物 Iba1 和卫星神经胶质细胞标志物 GFAP 共表达，但不与神经元标志物 PGP9.5 共表达，表明 TLR7 在小鼠或豚鼠的迷走神经或背根神经节中均不表达。相比之下，TLR7 抗体以不依赖 TLR7 的方式标记野生型和 TLR7 KO 小鼠中的中小型神经元。在小鼠中，甲型流感感染导致脾脏中的显着体重减轻和 TLR7 上调，但在迷走神经节中没有。TLR7 由巨噬细胞和卫星神经胶质细胞表达，但感觉神经节中的神经元不表达，这表明 TLR7 的神经调节作用是通过激活神经元相关支持细胞间接介导的，而不是通过直接激活神经元来介导。我们的数据还表明 TLR7 在神经元组织中的主要作用与抗病毒免疫无关。