J. Ishaque, E. Bienert, A. Manikandan, S. Allanki, L. Canes Esteve, J. Poeling, S. Guenther, D. Y. R. Stainier, S. T. Sossalla, A. Beisaw, S. Reischauer
Inflammation is essential for regeneration yet can also drive fibroinflammatory remodeling; what determines these opposing outcomes remains unclear. Comparative transcriptomic analyses revealed that injured mouse hearts activated a broad inflammatory program, whereas zebrafish hearts mounted a restricted response characterized by selective il11 induction. This divergence extended across tissues and species: the non-regenerative mammalian injuries examined shared an inflammatory signature distinct from regenerative vertebrate contexts. We identified the AP1 transcription factor Junb as an Il11 Stat3 dependent regulator that restrains inflammation during fin fold regeneration. Combined loss of junba and junbb amplified a mammalian-like inflammatory program, increased neutrophil recruitment and fibroinflammatory gene expression, and reduced proliferation and regenerative outgrowth. Strikingly, dexamethasone or ibuprofen substantially restored regeneration in Junb deficient zebrafish larvae, demonstrating that hyperinflammation is a major determinant of regenerative failure. Thus, the Il11 Stat3 Junb axis maintains a regeneration permissive inflammatory state preventing a regenerative response from shifting toward mammalian like fibroinflammation.