Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons

He, Long; Han, Guang; Wu, Shaogen; Du, Shouying; Zhang, Yang; Liu, Weili; Jiang, Bao‐Chun; Zhang, Luyao; Xia, Shangzhou; Jia, Shushan; Hannaford, Stephen; Xu, Ying; Tao, Yuan Xiang

doi:10.1016/j.bbi.2020.03.019

Cited by 47 publications

(84 citation statements)

References 51 publications

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“…The increased expression of Iba1, but not of GFAP, was attenuated by thalamic premicroinjection of Fgr siRNA in the Coll IV–treated mice ( Figure 8A ). Moreover, Coll IV microinjection activated NF-κB and ERK pathways as documented by the increased amounts of phosphorylated p65 (p-p65), a key member of NF-κB family ( 20 , 21 ), in the nuclear fraction and of phosphorylated ERK1/2 (p-ERK1/2) in the total cellular fraction, respectively, in the ipsilateral thalami of Fgr scrambled siRNA–treated mice on day 5 post–Coll IV microinjection ( Figure 8, B and C ). These increases were significantly inhibited by thalamic premicroinjection of Fgr siRNA in the Coll IV–treated mice ( Figure 8, B and C ).…”

Section: Resultsmentioning

confidence: 99%

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Huang¹,

Fu²,

Gao³

et al. 2020

JCI Insight

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Thalamic pain, a type of central poststroke pain, frequently occurs following ischemia/hemorrhage in the thalamus. Current treatment of this disorder is often ineffective, at least in part due to largely unknown mechanisms that underlie thalamic pain genesis. Here, we report that hemorrhage caused by microinjection of type IV collagenase or autologous whole blood into unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus increased the expression of Fgr, a member of the Src family nonreceptor tyrosine kinases, at both mRNA and protein levels in thalamic microglia. Pharmacological inhibition or genetic knockdown of thalamic Fgr attenuated the hemorrhage-induced thalamic injury on the ipsilateral side and the development and maintenance of mechanical, heat, and cold pain hypersensitivities on the contralateral side. Mechanistically, the increased Fgr participated in hemorrhage-induced microglial activation and subsequent production of TNF-α likely through activation of both NF-κB and ERK1/2 pathways in thalamic microglia. Our findings suggest that Fgr is a key player in thalamic pain and a potential target for the therapeutic management of this disorder.

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Section: Resultsmentioning

confidence: 99%

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Huang¹,

Fu²,

Gao³

et al. 2020

JCI Insight

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“…TLR8 is Upregulated in IB4 1 and CGRP 1 TG Neurons After pIONL and Contributes to the Maintenance of TNP TLRs, as one type of innate receptors, can recognize microbial pathogens and play an essential role in the initiation of innate immune responses [16]. In recent years, the role of TLRs in pain and itch has been widely investigated [17,18,35]. Several TLRs have been demonstrated to be expressed in glial cells and neurons in the DRG under chronic pain conditions [19,36].…”

Section: Discussionmentioning

confidence: 99%

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

et al. 2020

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Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca2+ concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.

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“…In the central nervous system, intrathecal injection of TLR7 agonists caused axonal injury and neuronal cell death in mice in vivo [10,11] and reduced dendrite growth in cultured mouse cortical neurons in vitro [12], suggesting TLR7 in uences cortical neurogenesis. Intradermal injection of TLR7 agonists also potentiated sensation of pain and itch in mice [13][14][15], suggesting TLR7 also has neuromodulatory effects on peripheral sensory nerve function. 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.…”

Section: Introductionmentioning

confidence: 94%

“…Commercial TLR7 antibodies label small and medium sensory neurons in a TLR7-independent manner Sections of wild type, TLR7 KO, and guinea pig dorsal root ganglia and vagal ganglia were immunolabeled with previously-cited commercial TLR7 antibodies [13,15,[30][31][32]. Tissue sections from wild type and TLR7 KO mice were processed simultaneously and reacted with DAB for the same duration to ensure equal treatment.…”

Section: Tlr7 Expression Increases During In Uenza a Infection In Moumentioning

confidence: 99%

“…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 con icting 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 ndings have complicated efforts to develop a mechanistic understanding of TLR7 function in nervous tissues.…”

Section: Introductionmentioning

confidence: 99%

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TLR7 Is Expressed by Support Cells, but Not Sensory Neurons, in Ganglia 

Proskocil

Wai

Lebold

et al. 2021

Preprint

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Background: Toll like receptor 7 (TLR7) is an innate immune receptor that detects viral single-stranded RNA and triggers 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 development of a mechanistic understanding of TLR7 function in nervous tissues.Methods: 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 mice, and in guinea pigs. In situ labeling was compared to immunohistochemistry using TLR7 antibody probes. Pulmonary afferent neurons in vagal ganglia were also specifically tested since respiratory viruses are a common TLR7 ligand. Guinea pig vagal afferents were labeled by intranasal instillation of wheat germ agglutinin, isolated using flow cytometry and analyzed for TLR7 by RT-PCR. The effects of influenza A infection on TLR7 expression in sensory ganglia and in spleen were also assessed.Results: In situ probes detected TLR7 in the spleens and in small support cells adjacent to sensory neurons in dorsal root and vagal ganglia in wild type mice and guinea pig, but not in TLR7 KO mice. TLR7 was co-expressed with the macrophage and satellite glial cell marker Iba1, but was absent in sensory nerves in vagal and dorsal root ganglia in both mice and guinea pigs. In contrast, a TLR7 antibody labeled small and medium-sized neurons in wild-type and TLR7 KO mice in a TLR7-independent manner. Wheat germ agglutinin-positive cells sorted by flow cytometry expressed both TLR7 and Iba1, indicating that TLR7-expressing support cells sort alongside neurons despite ganglia dissociation. Influenza A infection caused significant weight loss and upregulation of TLR7 in spleens, but not in vagal ganglia, in mice.Conclusion: 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 role in neuronal tissues is not primarily related to antiviral immunity.

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Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons

Cited by 47 publications

References 51 publications

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

TLR7 Is Expressed by Support Cells, but Not Sensory Neurons, in Ganglia

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Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons

Cited by 47 publications

References 51 publications

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

TLR7&nbsp;Is Expressed by Support Cells, but Not Sensory Neurons, in Ganglia&nbsp;

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TLR7 Is Expressed by Support Cells, but Not Sensory Neurons, in Ganglia