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Myeloid-specific tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses
Abhishek Guha1,2,3, Robert E Sorge4, Ying Si5,6,7
1Department of Neurology, University of Alabama at Birmingham, Civitan 545C, 1719 6th Avenue South, Birmingham, AL, 35294-0017, USA. abhishekguha@uabmc.edu.
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 inflammatory responses that drive postsurgical pain. Loss of TTP worsens pain and inflammation, while its presence alleviates these effects, revealing TTP as a therapeutic target.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Proinflammatory mediators like COX-2, IL-1β, IL-6, and TNF-α are key in postsurgical pain initiation.
- These mediators are regulated post-transcriptionally via adenine- and uridine-rich elements (ARE) in mRNA.
- Tristetraprolin (TTP), an ARE-binding protein (AUBP), degrades mRNA and silences translation of these mediators.
Purpose of the Study:
- To investigate the role of Tristetraprolin (TTP) in postsurgical pain and inflammation.
- To determine if TTP modulates peripheral, central, and systemic inflammatory responses following surgical injury.
Main Methods:
- Mice with myeloid-specific TTP knockout or knock-in models were used.
- Paw incision surgery was performed, followed by assessment of mechanical allodynia and thermal sensitivity.
- Inflammatory markers were analyzed in skin, dorsal root ganglia (DRG), spinal cord (L-SC), and circulation using qPCR, ELISA, and flow cytometry.
Main Results:
- TTP deletion exacerbated incisional pain, edema, and delayed wound healing, with increased macrophages and inflammatory mediators at the injury site.
- Enhanced inflammatory responses were observed in circulation, DRG, and L-SC persisting up to 7 days post-incision.
- TTP knock-in attenuated pain and inflammatory markers in skin, DRG, L-SC, and circulation.
Conclusions:
- TTP plays a crucial role in mitigating postsurgical pain by suppressing peripheral, central, and systemic inflammation.
- TTP represents a novel therapeutic target and mechanism for managing postsurgical pain.
