Enkephalin Production by Regulatory T Cells Modulates Basal Somatic Sensitivity in Mice

核心概念

Regulatory T cells produce the analgesic peptide enkephalin, which modulates basal somatic sensitivity in mice.

要約

This study investigates the role of regulatory T cells (Treg) in modulating pain sensitivity at steady state through the production of the analgesic peptide enkephalin.

Key highlights:

• A meta-analysis of Treg transcriptomes reveals that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, is among the top genes most enriched in Treg compared to conventional T cells.
• Penk expression in Treg is regulated by TNFR signaling and the transcription factor BATF.
• Penk is predominantly expressed by Treg, especially in peripheral tissues like the skin and colon, compared to other T cell subsets.
• Deletion of Penk specifically in Treg leads to heat hyperalgesia in mice, without affecting the immunosuppressive functions of Treg.
• Treg producing enkephalins are observed in close contact with CGRP-expressing nociceptive neurons in the skin, suggesting a direct modulation of pain sensation.

Overall, the results indicate that Treg-derived enkephalins play a key role in the endogenous regulation of basal somatic sensitivity, revealing a novel non-immune function of Treg.

統計

Penk ranks among the top 25 genes most enriched in Treg compared to conventional T cells.
Penk expression is highly correlated with the expression of TNFR family members and the transcription factor BATF in Treg.
Deletion of Penk in Treg leads to a 20% reduction in the median latency period to heat stimulation compared to wild-type controls.

引用

"Treg-derived enkephalins might regulate pain at multiple sites, including the DRG and peripheral tissues, such as the skin or the colon."
"Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin."
"Treg proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo."

抽出されたキーインサイト

Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice

by Aubert,N., P... 場所 www.biorxiv.org 09-15-2023

https://www.biorxiv.org/content/10.1101/2023.09.12.557326v3

深掘り質問

How do Treg-derived enkephalins modulate the electrophysiological properties of nociceptive neurons?

Enkephalins produced by Treg cells can modulate the electrophysiological properties of nociceptive neurons by acting on opioid receptors present on these neurons. When enkephalins bind to these receptors, they can inhibit the release of neurotransmitters involved in pain signaling, such as substance P and glutamate. This inhibition leads to a decrease in the excitability of nociceptive neurons, reducing the transmission of pain signals to the central nervous system. Additionally, enkephalins can also hyperpolarize nociceptive neurons, making it more difficult for them to reach the threshold for firing action potentials and transmitting pain signals. Overall, the production of enkephalins by Treg cells provides a mechanism for dampening pain signaling and modulating the sensitivity of nociceptive neurons.

What is the role of Treg-derived enkephalins in regulating visceral pain, given their high expression in the colon?

Treg-derived enkephalins play a crucial role in regulating visceral pain, especially in the colon, where they are highly expressed. Enkephalins act as endogenous opioids that can bind to opioid receptors on sensory neurons in the colon, inhibiting the release of pain neurotransmitters and reducing the excitability of these neurons. By modulating the activity of nociceptive neurons in the colon, enkephalins produced by Treg cells can alleviate visceral pain and contribute to maintaining homeostasis in the gastrointestinal tract. This regulatory mechanism helps to prevent excessive pain signaling in response to stimuli in the colon, thereby reducing discomfort and promoting overall gut health.

Could Treg-derived enkephalins be harnessed as a therapeutic approach to manage chronic pain conditions?

The production of enkephalins by Treg cells presents a promising avenue for the development of novel therapeutic approaches to manage chronic pain conditions. By leveraging the analgesic properties of enkephalins, researchers could potentially harness Treg-derived enkephalins to modulate pain sensitivity and alleviate chronic pain in patients. Strategies that enhance the production or activity of enkephalins, such as promoting Treg function or targeting specific pathways involved in enkephalin regulation, could be explored as potential treatments for chronic pain disorders. Additionally, the development of enkephalin-based therapies that target specific opioid receptors in pain pathways may offer a more targeted and effective approach to pain management, with potentially fewer side effects compared to traditional opioid medications. Further research into the mechanisms of enkephalin production and action by Treg cells is needed to fully realize the therapeutic potential of Treg-derived enkephalins in managing chronic pain conditions.