Abstract
BackgroundToll-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.MethodsTLR7 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.ResultsIn 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.ConclusionTLR7 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.
Highlights
Toll-like receptor 7 (TLR7) is a pattern-recognition receptor that detects single-stranded viral RNA genomes and triggers an innate immune response [1]
Intradermal injection of TLR7 agonists potentiated sensation of pain and itch in mice [13,14,15], suggesting TLR7 has neuromodulatory effects on peripheral sensory nerve function as well. Whether these effects are due to direct activation of neurons or mediated indirectly by second messengers released from TLR7-expressing support cells in ganglia, such as satellite glial cells and resident macrophages, is controversial
TLR7 is expressed by non-neuronal cells in dorsal root and vagal ganglia The specificity of RNA-specific mouse TLR7 probes was assessed in wild-type and TLR7 KO mice using in situ hybridization
Summary
Toll-like receptor 7 (TLR7) is a pattern-recognition receptor that detects single-stranded viral RNA genomes and triggers an innate immune response [1]. Intradermal injection of TLR7 agonists potentiated sensation of pain and itch in mice [13,14,15], suggesting TLR7 has neuromodulatory effects on peripheral sensory nerve function as well Whether these effects are due to direct activation of neurons or mediated indirectly by second messengers released from TLR7-expressing support cells in ganglia, such as satellite glial cells and resident macrophages, is controversial. Previous studies reported conflicting results regarding TLR7 expression in ganglia, with some showing neuronal TLR7 expression using commercially available TLR7 antibodies, while others reported either the presence or absence of neuronal TLR7 RNA expression using RT-PCR [13,14,15,16,17,18] These discordant findings have complicated efforts to develop a mechanistic understanding of TLR7 function in nervous tissues. This uncertainty has confounded the development of a mechanistic understanding of TLR7 function in nervous tissues
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