TGFβ-activated kinase 1 signaling controls acquisition of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction

TGFβ-activated kinase 1 signaling controls acquisition of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction | 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 Article TGFβ-activated kinase 1 signaling controls acquisition of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction Bradford Hill, Daniel Nguyen, Jonah Stephan, Robert Brainard, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6122755/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Organ health and function depend on communication between cell types to coordinate tissue growth and repair. Recent studies have indicated that fibroblasts are critical to this process; however, their role in regulating inflammatory responses to injury have remained ambiguous. Here, we demonstrate that transforming growth factor β-activated kinase 1 (TAK1) is a gatekeeper of the inflammatory cardiac fibroblast phenotype. We find that TAK1 propagates IL-1β and TNF-α signaling in cardiac fibroblasts and coordinates the synthesis and secretion of chemokines as well as inflammatory and pro-resolving lipid mediators. Deletion of TAK1 in fibroblasts decreased immune cell recruitment after MI, which was associated with improved cardiac structural and functional remodeling in male mice. Nevertheless, we found the effects of TAK1 deletion to be sexually dimorphic in nature, providing support to the idea that the protected phenotype of the female sex may be based in disparate immune and inflammatory responses. Moreover, TAK1 signaling controlled the acquisition of novel markers of the inflammatory fibroblast phenotype, having a biological basis in redox stress, chemokine and lipid mediator biosynthesis, metalloproteinase activity, and damage-associated molecular pattern recognition. Collectively, these results further resolve the nature and function of inflammatory cardiac fibroblasts in cardiac responses to injury and identify TAK1 signaling in fibroblasts as a potential target for therapy. Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Heart failure Biological sciences/Immunology/Cell death and immune response Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files StatisticalAnalysis2.26.2025FINAL.xlsx Detailed statistical tables Suppl.Fig.Tablecompiled2.26.25FINAL.pdf Supplementary Data and Tables Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6122755","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":424701454,"identity":"adbad8d3-ea86-4ded-97f0-cdee30568f2c","order_by":0,"name":"Bradford Hill","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie3QMUsDMRTA8VcKZgm6Pjl7/QopgfMK/TC5pS4OwoHcIBgp3CT6BcTPYJfOOQLtcuDaSVIEJwddxNF31dMlhRsd8ocsL/wgeQCh0D9M0MECoKexd2VckQL0aaTO0vbWT+pvoo2q8YcI7EIATFZiO99NjiO7WZviaaCjmTbZPcZixV7QCYyBzRboIeObqUxNnUt9VBFZoBSWJ0gPk8CX5z4iakii91JlGrMtyR4s7wsiNDlN/IR9YPVL7hrCnhtyqYevOwg944/ohsDIEVGA3EvG1zynvyhZNkQtUR5aviWjkk/z1Lcxzua0MTW4xZONe7uYxPuPK1d9FpPhAbPztW/LbXsdJqFQKBTq2heI32XR5KAg+AAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5332-8286","institution":"University of Louisville","correspondingAuthor":true,"prefix":"","firstName":"Bradford","middleName":"","lastName":"Hill","suffix":""},{"id":424701455,"identity":"2e43238f-ecd6-4681-9fd0-eab4c940a89f","order_by":1,"name":"Daniel Nguyen","email":"","orcid":"","institution":"University of 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Louisville","correspondingAuthor":false,"prefix":"","firstName":"Danielle","middleName":"","lastName":"Little","suffix":""},{"id":424701465,"identity":"7a8f94fb-c50a-45f0-a022-41500d66c71c","order_by":11,"name":"Nolan Boyd","email":"","orcid":"https://orcid.org/0000-0001-9537-6040","institution":"Louisville","correspondingAuthor":false,"prefix":"","firstName":"Nolan","middleName":"","lastName":"Boyd","suffix":""},{"id":424701466,"identity":"ebd75404-cb88-4f80-ba5a-6030bf1ac3ca","order_by":12,"name":"Richa Singhal","email":"","orcid":"","institution":"University of Louisville","correspondingAuthor":false,"prefix":"","firstName":"Richa","middleName":"","lastName":"Singhal","suffix":""},{"id":424701467,"identity":"18d17e30-8d9b-417f-925b-8055696361d6","order_by":13,"name":"Jason Hellmann","email":"","orcid":"","institution":"University of Louisville School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jason","middleName":"","lastName":"Hellmann","suffix":""},{"id":424701468,"identity":"74f09d24-b245-4eea-8542-3767e9e5ba43","order_by":14,"name":"Marcin Wysoczynski","email":"","orcid":"","institution":"University of Louisville","correspondingAuthor":false,"prefix":"","firstName":"Marcin","middleName":"","lastName":"Wysoczynski","suffix":""}],"badges":[],"createdAt":"2025-02-27 16:35:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6122755/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6122755/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78319596,"identity":"1f0090c8-402f-47f9-ae9d-a11d93dd7425","added_by":"auto","created_at":"2025-03-12 04:52:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":777403,"visible":true,"origin":"","legend":"\u003cp\u003eTAK1 propagates inflammatory signaling and regulates the synthesis of secreted \u0026nbsp;proteins in cardiac fibroblasts. a, Illustration of TAK1 signaling. b, Schematic of TAK1 conditional allele with LoxP sites flanking exon 2. Cre recombination yields a truncated TAK1 \u0026nbsp;product. c, d, Validation of Cre-mediated TAK1 truncation (TAK1∆) in isolated TAK1fl/fl cardiac \u0026nbsp;fibroblasts 3 (c) and 7 (d) days after adenovirus (Ad-CMV-iCre) treatment. e–h, Representative \u0026nbsp;immunoblots and densitometry of inflammatory and stress signaling proteins in control (Ad-CMV-LacZ) or iCre-pretreated TAK1fl/fl cardiac fibroblasts. Fibroblasts were treated without or with TNF-α (e, f) or IL-1β (g, h) for 30 min prior to cell lysis and collection. i, j, Evaluation of puromycin-tagged proteins in conditioned medium from control or TAK1 deficient fibroblasts following 48 h \u0026nbsp;of ligand stimulation. Data are mean ± SEM. For d–j, n = 3–5 biological replicates per group. \u0026nbsp;Statistical procedures: (f,h,j) two-way ANOVA with Šidák’s post-hoc. Experiments and blots were \u0026nbsp;processed in parallel and normalized to an anchor protein. Schematics in a,b were created using \u0026nbsp;BioRender (https://biorender.com).\u003c/p\u003e","description":"","filename":"Compiledfigures2.26.25FINAL1.png","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1/6c6b1bbbd987d18990983da3.png"},{"id":78319598,"identity":"1da6b0c7-bad4-4cff-9d59-b753c9dd30f3","added_by":"auto","created_at":"2025-03-12 04:52:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":843285,"visible":true,"origin":"","legend":"\u003cp\u003eFibroblast TAK1 deletion attenuates adverse structural and functional cardiac \u0026nbsp;remodeling following myocardial infarction in male mice. a, Experimental scheme of mice \u0026nbsp;subjected to MI injury with echocardiography acquisition at 7 and 28 d post-MI. b,c, Representative immunoblot (b) and densitometric quantification (c) of TAK1 knockdown from \u0026nbsp;cardiac fibroblasts isolated from tamoxifen-treated mice. Proteins were normalized to amido black \u0026nbsp;signal from stained membranes. n = 3–4 independent biological replicates per group, with males \u0026nbsp;and females pooled. d, Kaplan-Meier survival curves for Cre- and Cre+ TAK1fl/fl male (n = 49; 25 \u0026nbsp;Cre- , 24 Cre+ ) and female (n = 47; 22 Cre- , 25 Cre+) mice following MI. e,f, Echocardiographic \u0026nbsp;quantification of ejection fraction (EF; e) and cardiac output (CO; f) at 1 and 4 wk post-MI for \u0026nbsp;female and male mice. n = 10–17 biological replicates per group. g–j, Representative Picosirius \u0026nbsp;red staining of transverse myocardial sections (g, h) used for quantification of scar mass (i) and \u0026nbsp;width (j) from infarcted hearts. n = 9–15 biological replicates per group. Data are mean ± SEM. \u0026nbsp;Statistical procedures: Normality was assessed via Shapiro-Wilk test. (c) Parametric unpaired \u0026nbsp;student’s t-test. (d) log-rank (Mantel-Cox) test. (e, f) two-way ANOVA with Šidák’s post-hoc. (i, j) \u0026nbsp;Parametric unpaired student’s t-test or non-parametric Mann-Whitney U test were used as \u0026nbsp;appropriate. Schematics in a were created using BioRender (https://biorender.com).\u003c/p\u003e","description":"","filename":"Compiledfigures2.26.25FINAL2.png","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1/04636e0031f56606949b4a5c.png"},{"id":78319597,"identity":"bf6647bf-686c-4a4e-93cc-f4281eaafabc","added_by":"auto","created_at":"2025-03-12 04:52:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":543178,"visible":true,"origin":"","legend":"\u003cp\u003eFibroblast TAK1 deletion diminishes the abundance of immune cells in the heart \u0026nbsp;following MI. a, Schematic of study design assessing cardiac immune cell abundances 2, 3, and \u0026nbsp;5 d post-MI. b, Flow cytometric gating strategy for identification and quantification of immune cell \u0026nbsp;populations. c, Populations were quantified and normalized to wet tissue weight. n = 6–13 \u0026nbsp;biological replicates per group. Data are mean ± SEM. Statistical procedures: two-way ANOVA \u0026nbsp;with Šidák’s post-hoc. Schematics in a were created using BioRender (https://biorender.com).\u003c/p\u003e","description":"","filename":"Compiledfigures2.26.25FINAL3.png","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1/9d221cbafca4675e01dcae6a.png"},{"id":78319377,"identity":"be094f61-21a7-4d0c-b76c-6f57688a8676","added_by":"auto","created_at":"2025-03-12 04:44:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":234776,"visible":true,"origin":"","legend":"\u003cp\u003eThe IL-1β-mediated fibroblast secretome is coordinated via TAK1 signaling. \u0026nbsp;Isolated cardiac fibroblasts transduced with LacZ or iCre adenovirus were treated with TGFβ or \u0026nbsp;IL-1β for 48 h prior to conditioned medium collection. a, Heat map illustrating secreted proteins measured using quantitative cytokine/chemokine assay array (MD44; Evetechnologies). X = \u0026nbsp;outside of standard curve, n = 4 male biological replicates per group. b, c, Representative \u0026nbsp;immunoblot (b) and densitometry quantification (c) of cyclooxygenase 2 (COX2) abundance from \u0026nbsp;TAK1fl/fl and TAK1∆ fibroblasts following 48 h of IL-1β stimulation. Data are mean ± SEM. Proteins \u0026nbsp;were normalized to amido black signal from stained membranes. n = 5 male biological replicates \u0026nbsp;per group. d–f, Conditioned medium was collected for LC-MS/MS analysis of secreted lipid \u0026nbsp;mediators: PLS-DA plot (d), VIP score plot (e), and heatmap (f). n = 3 male biological replicates \u0026nbsp;per group. Statistical procedures: (a, c, f) two-way ANOVA with Šidák’s post-hoc test; (a) *# p\u0026lt;0.05, *IL-1β (LacZ vs iCre), # TGFβ (LacZ vs iCre); (f) *# p\u0026lt;0.05, *IL-1β (LacZ vs iCre), # CTRL \u0026nbsp;(LacZ vs iCre).\u003c/p\u003e","description":"","filename":"Compiledfigures2.26.25FINAL4.png","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1/3d19a2829a71c7e15c1b080e.png"},{"id":78319385,"identity":"e9c0df2b-9451-4ccd-acb0-95714edbfa5a","added_by":"auto","created_at":"2025-03-12 04:44:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":391889,"visible":true,"origin":"","legend":"\u003cp\u003eTAK1 controls acquisition of an inflammatory fibroblast phenotype. a, Principal \u0026nbsp;component analysis of gene expression from LacZ or iCre transduced cells following 24 h of \u0026nbsp;ligand stimulation. b, Plot indicating the number of differentially expressed genes across \u0026nbsp;comparison groups (log2FC \u0026gt; 0; q-value \u0026lt; 0.05). c, Heat map visualization of the log2FC values \u0026nbsp;for genes associated with fibrotic processes, inflammatory regulation, and lipid mediator \u0026nbsp;synthesis. *q \u0026lt; 0.01. d–g, Representative immunoblots (d) and densitometric quantification (e– g) of iNOS, COX2, and MMP3 levels from TAK1fl/fl and TAK1∆ fibroblasts following 48 h of ligand \u0026nbsp;stimulation. Data are mean ± SEM. Proteins were normalized to amido black signal from stained \u0026nbsp;membranes. Experiments and blots were processed in parallel and normalized to an anchor \u0026nbsp;protein. For a–g, n = 4 male biological replicates per group. Statistical procedures: (e–g) two-way \u0026nbsp;ANOVA with Šidák’s post-hoc test.\u003c/p\u003e","description":"","filename":"Compiledfigures2.26.25FINAL5.png","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1/d6b9c914c73d0dac33d31261.png"},{"id":78320424,"identity":"78390a4b-55c2-4ba2-a2a8-eafac74a7849","added_by":"auto","created_at":"2025-03-12 05:00:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2208381,"visible":true,"origin":"","legend":"Article File","description":"","filename":"NguyenDetal.NatureCommuTAK1paper2.26.2025FINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1_covered_ee11f20b-75cd-482d-98a1-3b6b2d9a30ef.pdf"},{"id":78319387,"identity":"0d0e06d3-5444-4154-852d-1fb0c409255b","added_by":"auto","created_at":"2025-03-12 04:44:34","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":78152,"visible":true,"origin":"","legend":"Detailed statistical tables","description":"","filename":"StatisticalAnalysis2.26.2025FINAL.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1/26dee1744acbffa3a5d9b053.xlsx"},{"id":78319382,"identity":"94e70dec-5358-4322-9866-1c3310586547","added_by":"auto","created_at":"2025-03-12 04:44:29","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":21609955,"visible":true,"origin":"","legend":"Supplementary Data and Tables","description":"","filename":"Suppl.Fig.Tablecompiled2.26.25FINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6122755/v1/3975da704e26acc7692591cc.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"TGFβ-activated kinase 1 signaling controls acquisition of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6122755/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6122755/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Organ health and function depend on communication between cell types to coordinate tissue growth and repair. Recent studies have indicated that fibroblasts are critical to this process; however, their role in regulating inflammatory responses to injury have remained ambiguous. Here, we demonstrate that transforming growth factor β-activated kinase 1 (TAK1) is a gatekeeper of the inflammatory cardiac fibroblast phenotype. We find that TAK1 propagates IL-1β and TNF-α signaling in cardiac fibroblasts and coordinates the synthesis and secretion of chemokines as well as inflammatory and pro-resolving lipid mediators. Deletion of TAK1 in fibroblasts decreased immune cell recruitment after MI, which was associated with improved cardiac structural and functional remodeling in male mice. Nevertheless, we found the effects of TAK1 deletion to be sexually dimorphic in nature, providing support to the idea that the protected phenotype of the female sex may be based in disparate immune and inflammatory responses. Moreover, TAK1 signaling controlled the acquisition of novel markers of the inflammatory fibroblast phenotype, having a biological basis in redox stress, chemokine and lipid mediator biosynthesis, metalloproteinase activity, and damage-associated molecular pattern recognition. Collectively, these results further resolve the nature and function of inflammatory cardiac fibroblasts in cardiac responses to injury and identify TAK1 signaling in fibroblasts as a potential target for therapy.","manuscriptTitle":"TGFβ-activated kinase 1 signaling controls acquisition of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-12 04:44:24","doi":"10.21203/rs.3.rs-6122755/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f2af4719-4649-445c-9861-41400c04670e","owner":[],"postedDate":"March 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":45263035,"name":"Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Heart failure"},{"id":45263036,"name":"Biological sciences/Immunology/Cell death and immune response"}],"tags":[],"updatedAt":"2026-03-17T15:47:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-12 04:44:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6122755","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6122755","identity":"rs-6122755","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}