Loss of direct adrenergic innervation after peripheral nerve injury causes lymph node expansion through IFN-γ

Peripheral nerve injury can cause debilitating disease and immune cell–mediated destruction of the affected nerve. While the focus has been on the nerve-regenerative response, the effect of loss of innervation on lymph node function is unclear. Here, we show that the popliteal lymph node (popLN) receives direct neural input from the sciatic nerve and that sciatic denervation causes lymph node expansion. Loss of sympathetic, adrenergic tone induces the expression of IFN-γ in LN CD8 T cells, which is responsible for LN expansion. Surgery-induced IFN-γ expression and expansion can be rescued by β2 adrenergic receptor agonists but not sensory nerve agonists. These data demonstrate the mechanisms governing the pro-inflammatory effect of loss of direct adrenergic input on lymph node function.

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Peripheral nerve injury induces endoneurial expression of IFN-γ, IL-10 and TNF-α mRNA

Journal of Neuroimmunology ◽

10.1016/s0165-5728(99)00154-x ◽

2000 ◽

Vol 102 (1) ◽

pp. 17-25 ◽

Cited By ~ 80

Author(s):

H.S Taskinen ◽

T Olsson ◽

A Bucht ◽

M Khademi ◽

L Svelander ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Tnf Α ◽

Ifn Γ

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The voltage-gated proton channel Hv1 promotes microglia-astrocyte communication and neuropathic pain after peripheral nerve injury

Molecular Brain ◽

10.1186/s13041-021-00812-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jiyun Peng ◽

Min-Hee Yi ◽

Heejin Jeong ◽

Przemyslaw Peter McEwan ◽

Jiaying Zheng ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Molecular Mechanisms ◽

Proton Channel ◽

Astrocyte Activation ◽

Voltage Gated ◽

Ifn Γ

AbstractActivation of spinal cord microglia contributes to the development of peripheral nerve injury-induced neuropathic pain. However, the molecular mechanisms underlying microglial function in neuropathic pain are not fully understood. We identified that the voltage-gated proton channel Hv1, which is functionally expressed in spinal microglia, was significantly increased after spinal nerve transection (SNT). Hv1 mediated voltage-gated proton currents in spinal microglia and mice lacking Hv1 (Hv1 KO) display attenuated pain hypersensitivities after SNT compared with wildtype (WT) mice. In addition, microglial production of reactive oxygen species (ROS) and subsequent astrocyte activation in the spinal cord was reduced in Hv1 KO mice after SNT. Cytokine screening and immunostaining further revealed that IFN-γ expression was compromised in spinal astrocytes in Hv1 KO mice. These results demonstrate that Hv1 proton channel contributes to microglial ROS production, astrocyte activation, IFN-γ upregulation, and subsequent pain hypersensitivities after SNT. This study suggests Hv1-dependent microglia-astrocyte communication in pain hypersensitivities and identifies Hv1 as a novel therapeutic target for alleviating neuropathic pain.

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End-to-side neurorrhaphy repairs peripheral nerve injury: sensory nerve induces motor nerve regeneration

Neural Regeneration Research ◽

10.4103/1673-5374.217350 ◽

2017 ◽

Vol 12 (10) ◽

pp. 1703 ◽

Cited By ~ 2

Author(s):

Yu-dong Gu ◽

Qing Yu ◽

She-hong Zhang ◽

Tao Wang ◽

Feng Peng ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Motor Nerve ◽

Sensory Nerve

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Use of Integrated Optical Clearing and 2-Photon Imaging to Investigate Sex Differences in Neuroimmune Interactions After Peripheral Nerve Injury

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.624201 ◽

2021 ◽

Vol 9 ◽

Author(s):

Thomas A. Szabo-Pardi ◽

Umar M. Syed ◽

Zachary W. Castillo ◽

Michael D. Burton

Keyword(s):

Sex Differences ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Immune Cell ◽

Sexual Dimorphisms ◽

Bidirectional Signaling ◽

Integrated Optical ◽

Size And Morphology ◽

Peripheral Leukocytes

Peripheral nerve injury induces a myriad of immune-derived symptoms that negatively impacts pain, depression, and overall quality of life. Neuroimmune differences underlie sexual dimorphisms in various pain states. The innate immune system is a source of these sex differences, which promotes inflammation and pro-nociception through bidirectional signaling with the nervous system. Spatiotemporal interactions between leukocytes and sensory neurons could hold the key to explain ascribed differences between sexes. To date, studies have found it difficult to display these interactions. We are poised to answer important questions regarding the recruitment of peripheral leukocytes to key tissues of the pain system, the dorsal root ganglia (DRG) and sciatic nerve after nerve injury. We optically clear whole DRGs and sciatic nerves and concomitantly use multi-photon microscopy and transgenic reporter lines, to visualize leukocyte dynamics involved in neuropathic pain development following nerve injury. We observed robust sexual dimorphisms in leukocyte recruitment to the lumbar DRGs after nerve injury. We also assessed immune cell size and morphology to understand activation states in the context of nervous tissue inflammation. The altered mechanisms by which the male and female immune systems respond to nerve injury are still topics of further research, however; the continued use of next-generation imaging with advanced whole tissue image analysis remains an important tool in understanding the reciprocal interactions between neuronal and non-neuronal cells.

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