{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T07:52:47Z","timestamp":1781509967828,"version":"3.54.1"},"reference-count":47,"publisher":"The Company of Biologists","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32HD007491"],"award-info":[{"award-number":["T32HD007491"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM142950"],"award-info":[{"award-number":["R35GM142950"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007747","name":"University of Utah","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007747","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Heart injury triggers a robust cellular response in zebrafish, characterized by neovascularization, immune cell activation, and the infiltration of proliferative cardiomyocytes that collectively lead to scarless regeneration. Upon injury, damage-associated molecular patterns are released by dying cells and injured extracellular matrix. These molecules bind to pattern recognition receptors on various cell types, promoting inflammation and immune cell recruitment by upregulating chemokines and pro-inflammatory cytokines. We previously identified the activation of injury-induced interferon signaling as a distinguishing feature between the regenerative zebrafish and non-regenerative medaka. Here, we establish interferon-\u03a61 (IFN\u03c61) as the primary driver of interferon signaling after zebrafish heart injury. IFN\u03c61 expression is induced hours after injury and directs interferon-stimulated gene expression, which peaks at 3\u2005days post-injury. This response is lost in ifnphi1 mutants, which disrupt IFN\u03c61 expression. ifnphi1 mutants have reduced neutrophil recruitment to the injured myocardium, while macrophages and neovascularization are unaffected. By studying later stages of regeneration, we find that ifnphi1 mutant hearts have a modest defect in fibrotic tissue resolution. Collectively, these findings uncover a critical early signaling cascade during the inflammatory response to heart injury and provide new insights into the mechanisms that choreograph zebrafish heart regeneration.<\/jats:p>","DOI":"10.1242\/bio.062374","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:34:07Z","timestamp":1779784447000},"source":"Crossref","is-referenced-by-count":0,"title":["Interferon signaling is required for early neutrophil recruitment after zebrafish heart injury"],"prefix":"10.1242","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2918-5748","authenticated-orcid":false,"given":"Alexis V.","family":"Schmid","sequence":"first","affiliation":[{"name":"School of Biological Sciences, University of Utah 1 , Salt Lake City, UT, 84112 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3978-6058","authenticated-orcid":false,"given":"James A.","family":"Gagnon","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Utah 1 , Salt Lake City, UT, 84112 ,","place":["USA"]},{"name":"Henry Eyring Center for Cell & Genome Science, University of Utah 2 , Salt Lake City, 84112 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"2026061503073621600_BIO062374C1","doi-asserted-by":"publisher","first-page":"100023","DOI":"10.1016\/j.cytox.2020.100023","article-title":"IFN-\u03b3 and CIITA modulate IL-6 expression in skeletal muscle","volume":"2","author":"Adhikari","year":"2020","journal-title":"Cytokine X"},{"key":"2026061503073621600_BIO062374C2","doi-asserted-by":"publisher","first-page":"3924","DOI":"10.4049\/jimmunol.0901495","article-title":"The two groups of zebrafish virus-induced interferons signal via distinct receptors with specific and shared chains","volume":"183","author":"Aggad","year":"2009","journal-title":"J. Immunol."},{"key":"2026061503073621600_BIO062374C3","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1016\/j.cub.2020.04.031","article-title":"Linking virus discovery to immune responses visualized during zebrafish infections","volume":"30","author":"Balla","year":"2020","journal-title":"Curr. Biol."},{"key":"2026061503073621600_BIO062374C4","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1093\/cvr\/cvz221","article-title":"Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish","volume":"116","author":"Bevan","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"2026061503073621600_BIO062374C5","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/imcb.12241","article-title":"Neutrophil\u2013macrophage cooperation and its impact on tissue repair","volume":"97","author":"Bouchery","year":"2019","journal-title":"Immunol. Cell Biol."},{"key":"2026061503073621600_BIO062374C6","doi-asserted-by":"publisher","first-page":"e0215592","DOI":"10.1371\/journal.pone.0215592","article-title":"A transgenic zebrafish line for in vivo visualisation of neutrophil myeloperoxidase","volume":"14","author":"Buchan","year":"2019","journal-title":"PLoS ONE"},{"key":"2026061503073621600_BIO062374C7","doi-asserted-by":"publisher","first-page":"bio060156","DOI":"10.1242\/bio.060156","article-title":"Distinct features of the regenerating heart uncovered through comparative single-cell profiling","volume":"13","author":"Carey","year":"2024","journal-title":"Biol. Open"},{"key":"2026061503073621600_BIO062374C8","doi-asserted-by":"publisher","first-page":"eabd9502","DOI":"10.1126\/sciadv.abd9502","article-title":"Exercise mimetics and JAK inhibition attenuate IFN-\u03b3\u2013induced wasting in engineered human skeletal muscle","volume":"7","author":"Chen","year":"2021","journal-title":"Sci. Adv."},{"key":"2026061503073621600_BIO062374C9","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1038\/s41467-022-28645-6","article-title":"Identification and establishment of type IV interferon and the characterization of interferon-\u03c5 including its class II cytokine receptors IFN-\u03c5R1 and IL-10R2","volume":"13","author":"Chen","year":"2022","journal-title":"Nat. Commun."},{"key":"2026061503073621600_BIO062374C10","doi-asserted-by":"publisher","first-page":"C1183","DOI":"10.1152\/ajpcell.00568.2007","article-title":"Endogenous interferon-\u03b3 is required for efficient skeletal muscle regeneration","volume":"294","author":"Cheng","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"2026061503073621600_BIO062374C11","doi-asserted-by":"publisher","first-page":"3823","DOI":"10.1038\/s41467-025-59169-4","article-title":"Border-zone cardiomyocytes and macrophages regulate extracellular matrix remodeling to promote cardiomyocyte protrusion during cardiac regeneration","volume":"16","author":"Constanty","year":"2025","journal-title":"Nat. Commun."},{"key":"2026061503073621600_BIO062374C12","doi-asserted-by":"publisher","first-page":"2698","DOI":"10.1093\/eurheartj\/ehac153","article-title":"Adult T-cells impair neonatal cardiac regeneration","volume":"43","author":"Dolejsi","year":"2022","journal-title":"Eur. Heart J."},{"key":"2026061503073621600_BIO062374C13","doi-asserted-by":"publisher","first-page":"e49","DOI":"10.1182\/blood-2010-10-314120","article-title":"Mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish","volume":"117","author":"Ellett","year":"2011","journal-title":"Blood"},{"key":"2026061503073621600_BIO062374C14","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1161\/CIRCRESAHA.121.319929","article-title":"A vegfc-Emilin2a-Cxcl8a signaling axis required for zebrafish cardiac regeneration","volume":"130","author":"El-Sammak","year":"2022","journal-title":"Circ. Res."},{"key":"2026061503073621600_BIO062374C15","doi-asserted-by":"publisher","first-page":"dev204395","DOI":"10.1242\/dev.204395","article-title":"Nr4a1 modulates inflammation and heart regeneration in zebrafish","volume":"152","author":"Feng","year":"2025","journal-title":"Development"},{"key":"2026061503073621600_BIO062374C16","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.tig.2013.07.003","article-title":"The zebrafish as a model for complex tissue regeneration","volume":"29","author":"Gemberling","year":"2013","journal-title":"Trends Genet."},{"key":"2026061503073621600_BIO062374C17","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s00441-009-0908-5","article-title":"Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model","volume":"339","author":"Gong","year":"2010","journal-title":"Cell Tissue Res."},{"key":"2026061503073621600_BIO062374C18","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1038\/nprot.2012.025","article-title":"Cryoinjury as a myocardial infarction model for the study of cardiac regeneration in the zebrafish","volume":"7","author":"Gonz\u00e1lez-Rosa","year":"2012","journal-title":"Nat. Protoc."},{"key":"2026061503073621600_BIO062374C19","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1242\/dev.060897","article-title":"Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish","volume":"138","author":"Gonz\u00e1lez-Rosa","year":"2011","journal-title":"Development"},{"key":"2026061503073621600_BIO062374C20","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1002\/reg2.83","article-title":"Zebrafish heart regeneration: 15 years of discoveries","volume":"4","author":"Gonz\u00e1lez-Rosa","year":"2017","journal-title":"Regeneration"},{"key":"2026061503073621600_BIO062374C21","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1038\/s44161-024-00538-5","article-title":"The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration","volume":"3","author":"Goumenaki","year":"2024","journal-title":"Nat. Cardiovasc. Res."},{"key":"2026061503073621600_BIO062374C22","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.4103\/1673-5374.306059","article-title":"Inflammation induces zebrafish regeneration","volume":"16","author":"Iribarne","year":"2021","journal-title":"Neural Regen. R."},{"key":"2026061503073621600_BIO062374C23","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.3389\/fimmu.2019.01784","article-title":"The CXCL12\/CXCR4 signaling axis retains neutrophils at inflammatory sites in zebrafish","volume":"10","author":"Isles","year":"2019","journal-title":"Front. Immunol."},{"key":"2026061503073621600_BIO062374C24","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.actbio.2017.01.056","article-title":"Promoting tissue regeneration by modulating the immune system","volume":"53","author":"Julier","year":"2017","journal-title":"Acta Biomater."},{"key":"2026061503073621600_BIO062374C25","doi-asserted-by":"publisher","first-page":"e0190353","DOI":"10.1371\/journal.pone.0190353","article-title":"Targeted deletion of the zebrafish actin-bundling protein L-plastin (lcp1)","volume":"13","author":"Kell","year":"2018","journal-title":"PLoS ONE"},{"key":"2026061503073621600_BIO062374C26","doi-asserted-by":"publisher","first-page":"e53403","DOI":"10.7554\/eLife.53403","article-title":"Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes","volume":"9","author":"Kuil","year":"2020","journal-title":"eLife"},{"key":"2026061503073621600_BIO062374C27","doi-asserted-by":"publisher","first-page":"e25605","DOI":"10.7554\/eLife.25605","article-title":"Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration","volume":"6","author":"Lai","year":"2017","journal-title":"eLife"},{"key":"2026061503073621600_BIO062374C28","doi-asserted-by":"publisher","first-page":"eabi5253","DOI":"10.1126\/sciadv.abi5253","article-title":"Interferon \u03b2 drives intestinal regeneration after radiation","volume":"7","author":"Leibowitz","year":"2021","journal-title":"Sci. Adv."},{"key":"2026061503073621600_BIO062374C29","doi-asserted-by":"publisher","first-page":"25353","DOI":"10.1074\/jbc.M112.349126","article-title":"Live imaging reveals differing roles of macrophages and neutrophils during zebrafish tail fin regeneration *","volume":"287","author":"Li","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026061503073621600_BIO062374C30","doi-asserted-by":"publisher","DOI":"10.64898\/2026.03.18.712551","article-title":"IFN-\u03b3-Dependent macrophage reprogramming coordinates inflammatory resolution and matrix remodeling in heart regeneration","author":"Lim","year":"2026","journal-title":"bioRxiv"},{"key":"2026061503073621600_BIO062374C31","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1161\/CIRCRESAHA.123.323071","article-title":"Neutrophils for Revascularization Require Activation of CCR6 and CCL20 by TNF\u03b1","volume":"133","author":"L\u00f6rchner","year":"2023","journal-title":"Circ. Res."},{"key":"2026061503073621600_BIO062374C32","doi-asserted-by":"publisher","first-page":"49","DOI":"10.3390\/jcdd8050049","article-title":"The zebrafish cardiac endothelial cell\u2014roles in development and regeneration","volume":"8","author":"Lowe","year":"2021","journal-title":"J. Cardiovasc. Dev. Dis."},{"key":"2026061503073621600_BIO062374C33","doi-asserted-by":"publisher","first-page":"1570582","DOI":"10.3389\/fcvm.2025.1570582","article-title":"Macrophages and cardiac lesion in zebrafish: What can single-cell RNA sequencing reveal?","volume":"12","author":"Luz","year":"2025","journal-title":"Front. Cardiovas. Med."},{"key":"2026061503073621600_BIO062374C34","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1755-1536-6-11","article-title":"Neutrophil roles in left ventricular remodeling following myocardial infarction","volume":"6","author":"Ma","year":"2013","journal-title":"Fibrogenesis Tissue Repair"},{"key":"2026061503073621600_BIO062374C35","doi-asserted-by":"publisher","first-page":"11237","DOI":"10.1073\/pnas.1605431113","article-title":"Fast revascularization of the injured area is essential to support zebrafish heart regeneration","volume":"113","author":"Mar\u00edn-Juez","year":"2016","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026061503073621600_BIO062374C36","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s41419-018-0710-y","article-title":"Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-\u03baB activation","volume":"9","author":"Marwick","year":"2018","journal-title":"Cell Death Dis."},{"key":"2026061503073621600_BIO062374C38","doi-asserted-by":"publisher","first-page":"e2979-e2979","DOI":"10.1038\/cddis.2017.374","article-title":"TNF signaling and macrophages govern fin regeneration in zebrafish larvae","volume":"8","author":"Nguyen-Chi","year":"2017","journal-title":"Cell Death Dis."},{"key":"2026061503073621600_BIO062374C39","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s11357-007-9043-y","article-title":"Neutrophil depletion delays wound repair in aged mice","volume":"30","author":"Nishio","year":"2008","journal-title":"AGE"},{"key":"2026061503073621600_BIO062374C40","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.ydbio.2024.01.011","article-title":"Neutrophils facilitate the epicardial regenerative response after zebrafish heart injury","volume":"508","author":"Peterson","year":"2024","journal-title":"Dev. Biol."},{"key":"2026061503073621600_BIO062374C41","doi-asserted-by":"publisher","first-page":"2188","DOI":"10.1126\/science.1077857","article-title":"Heart regeneration in Zebrafish","volume":"298","author":"Poss","year":"2002","journal-title":"Science"},{"key":"2026061503073621600_BIO062374C42","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s12872-023-03231-w","article-title":"The global prevalence of myocardial infarction: a systematic review and meta-analysis","volume":"23","author":"Salari","year":"2023","journal-title":"BMC Cardiovasc. Disord."},{"key":"2026061503073621600_BIO062374C44","doi-asserted-by":"publisher","first-page":"4188","DOI":"10.1073\/pnas.1716713115","article-title":"Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart","volume":"115","author":"S\u00e1nchez-Iranzo","year":"2018","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026061503073621600_BIO062374C45","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1146\/annurev-immunol-032713-120231","article-title":"Interferon-stimulated genes: a complex web of host defenses","volume":"32","author":"Schneider","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"2026061503073621600_BIO062374C46","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1523\/JNEUROSCI.4918-08.2009","article-title":"Depletion of Ly6G\/Gr-1 leukocytes after spinal cord injury in mice alters wound healing and worsens neurological outcome","volume":"29","author":"Stirling","year":"2009","journal-title":"J. Neurosci."},{"key":"2026061503073621600_BIO062374C47","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1186\/s12859-021-04344-9","article-title":"CellProfiler 4: improvements in speed, utility and usability","volume":"22","author":"Stirling","year":"2021","journal-title":"BMC Bioinformatics"},{"key":"2026061503073621600_BIO062374C48","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1089\/wound.2012.0383","article-title":"Neutrophils and wound repair: positive actions and negative reactions","volume":"2","author":"Wilgus","year":"2013","journal-title":"Adv. Wound Care"},{"key":"2026061503073621600_BIO062374C49","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1073\/pnas.1311705111","article-title":"Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration","volume":"111","author":"Zhao","year":"2014","journal-title":"Proc. Natl Acad. Sci. USA"}],"container-title":["Biology Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/bio\/article-pdf\/doi\/10.1242\/bio.062374\/3701039\/bio062374.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/bio\/article-pdf\/doi\/10.1242\/bio.062374\/3704289\/bio062374.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/bio\/article-pdf\/doi\/10.1242\/bio.062374\/3704289\/bio062374.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T07:07:42Z","timestamp":1781507262000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/bio\/article\/15\/6\/bio062374\/371963\/Interferon-signaling-is-required-for-early"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":47,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6,15]]}},"URL":"https:\/\/doi.org\/10.1242\/bio.062374","relation":{},"ISSN":["2046-6390"],"issn-type":[{"value":"2046-6390","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]},"article-number":"bio062374"}}