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Myeloid-specific Tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses
Abhishek Guha1,2,3, Robert E Sorge4, Ying Si1,2,3
1Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA, 35294.
Background:
Proinflammatory mediators including COX-2, IL-1β, IL-6, and TNF-α, play major roles in the initiation of postsurgical pain. Produced primarily by activated macrophages and microglia, these mediators drive hyperexcitation of nociceptors and promote peripheral and central pain sensitization. Post-transcriptional RNA regulation is a major control point for these mediators, centering around adenine- and uridine-rich elements (ARE) in the 3' untranslated regions of their mRNA transcripts. The ARE governs RNA stability and translational efficiency through an interaction with ARE-specific RNA binding proteins (AUBP). Tristetraprolin (TTP) is an AUBP that promotes RNA degradation and translational silencing of these mediators to suppress inflammatory responses.
Methods:
Mice with myeloid-specific TTP knockout or TTP knock-in underwent paw incision and were assessed for mechanical allodynia and thermal sensitivity. Molecular and cellular inflammatory responses were monitored at the site of incision, dorsal root ganglia (DRG) and lumbar spinal cord (L-SC) by qPCR, ELISA, immunohistochemistry and/or flow cytometry.
Results:
TTP deletion exacerbated post-incisional allodynic pain in parallel with increased edema at the site of injury and delayed wound healing but without significant effects on thermal sensitivity. There was an increase in infiltrating macrophages at the incisional site, particularly at the dermal-epidermal junction, in parallel with a robust increase in proinflammatory/pronociceptive mediators. An enhanced inflammatory response was also detected in the circulation, ipsilateral DRG and L-SC which persisted through post-incisional day 7. Conversely, TTP knock-in mice showed attenuation of allodynic pain and inflammatory responses in skin, DRG, L-SC, and circulation.
Conclusion:
TTP plays a critical role in mitigating postsurgical pain by tamping down peripheral, central and systemic inflammatory responses, thus identifying a new target and mechanism for future development of pain therapeutics.
Insights
Tristetraprolin (TTP) suppresses postsurgical pain by reducing inflammation. Deleting TTP worsened pain and inflammation, while increasing TTP reduced it, highlighting TTP as a therapeutic target.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Proinflammatory mediators (COX-2, IL-1β, IL-6, TNF-α) initiate postsurgical pain.
- These mediators are regulated post-transcriptionally via adenine- and uridine-rich elements (ARE) in mRNA.
- Tristetraprolin (TTP), an ARE-binding protein, degrades mRNA and silences translation of these mediators.
Purpose of the Study:
- To investigate the role of TTP in postsurgical pain.
- To determine TTP's impact on inflammatory responses in a mouse model.
Main Methods:
- Mice with myeloid-specific TTP knockout or knock-in were subjected to paw incision.
- Mechanical allodynia and thermal sensitivity were assessed.
- Inflammatory responses were monitored in skin, dorsal root ganglia (DRG), and spinal cord (L-SC).
Main Results:
- TTP deletion exacerbated incisional pain, increased edema, and delayed wound healing.
- TTP deletion led to increased macrophages and proinflammatory mediators at the injury site and systemically.
- TTP knock-in attenuated pain and inflammatory responses.
Conclusions:
- TTP is critical for mitigating postsurgical pain.
- TTP suppresses peripheral, central, and systemic inflammatory responses.
- TTP represents a potential therapeutic target for pain management.
