Myeloid-specific Tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses

Myeloid-specific Tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Myeloid-specific Tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses Abhishek Guha, Robert E Sorge, Ying Si, Reed Smith, Sohail M Baig, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7244841/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2025 Read the published version in Inflammation Research → Version 2 posted 8 You are reading this latest preprint version Show more versions Abstract 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. postsurgical pain allodynia tristetraprolin proinflammatory mediators RNA regulation AU-rich element macrophages microglia Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementaryinformationrevised10222025.pdf Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2025 Read the published version in Inflammation Research → Version 2 posted Editorial decision: Accepted 03 Nov, 2025 Reviews received at journal 03 Nov, 2025 Reviewers agreed at journal 27 Oct, 2025 Reviews received at journal 24 Oct, 2025 Reviewers agreed at journal 24 Oct, 2025 Reviewers invited by journal 24 Oct, 2025 Submission checks completed at journal 23 Oct, 2025 First submitted to journal 22 Oct, 2025 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7244841","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":535848337,"identity":"df11d8f2-02e5-47bb-95b7-f10eca91eea6","order_by":0,"name":"Abhishek Guha","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Abhishek","middleName":"","lastName":"Guha","suffix":""},{"id":535848338,"identity":"c70f6bf9-48be-4774-8d59-747a301def5c","order_by":1,"name":"Robert E Sorge","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"E","lastName":"Sorge","suffix":""},{"id":535848339,"identity":"41a4101f-6fea-41d5-9843-0e11f8aab785","order_by":2,"name":"Ying Si","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Si","suffix":""},{"id":535848340,"identity":"cf3032ed-d331-4121-97ee-f611052ed575","order_by":3,"name":"Reed Smith","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Reed","middleName":"","lastName":"Smith","suffix":""},{"id":535848341,"identity":"9db68dcd-af10-4833-b3b8-b536d53b3374","order_by":4,"name":"Sohail M Baig","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Sohail","middleName":"M","lastName":"Baig","suffix":""},{"id":535848342,"identity":"2c442510-6b5f-422a-8597-2969d3aec1ad","order_by":5,"name":"Mohammed Amir Husain","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Mohammed","middleName":"Amir","lastName":"Husain","suffix":""},{"id":535848343,"identity":"de326547-18e0-48c6-9795-3192554d03c9","order_by":6,"name":"Stacie K. 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responses","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"inflammation-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"inre","sideBox":"Learn more about [Inflammation Research](http://link.springer.com/journal/11)","snPcode":"11","submissionUrl":"https://submission.nature.com/new-submission/11/3","title":"Inflammation Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"postsurgical pain, allodynia, tristetraprolin, proinflammatory mediators, RNA regulation, AU-rich element, macrophages, microglia","lastPublishedDoi":"10.21203/rs.3.rs-7244841/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7244841/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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.\nMethods: 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.\nResults: 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.\nConclusion: 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.","manuscriptTitle":"Myeloid-specific Tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-10-31 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