Junb acts downstream of the Il-11/Stat3 signaling axis to limit damage induced inflammation in the zebrafish tissue regeneration model

With few exceptions, the predominant mode of damaged tissue repair in mammals is scarring and healing due to their limited regenerative capabilities. Consequently, injury results in reduced organ function long term and is a major contributor to the severity and morbidity observed in a plethora of human diseases, including the heart.  While low regenerative capacity is widespread among mammals it is not a general trait of vertebrates. The zebrafish (Danio rerio) is known for its high regenerative capacity, where damage to organs like the heart or extremities like the fins leads to a regenerative response resulting in complete refunctionalization. Interleukin 11 (Il11) signalling in conjunction with the downstream target junb was identified as a key regulatory pathway in zebrafish heart regeneration. Junb functions as a part of the dimeric activator protein 1 complex (AP-1) where it dimerises with other Proteins from the Fos, ATF or Maf family to be able to bind DNA and fulfil transcription factor functions. Here we show that cardiac injury in the zebrafish leads to an increased expression of junba / junbb, this increase is reduced in fish lacking the Interleukin 11 receptor (il11ra^-/-) and are unable to regenerate. Here, using junba and junbb mutant alleles, we investigate the role of Junb during regeneration by utilizing the zebrafish larval fin fold  as a model for tissue regeneration. Employing a combination of genetic models and drug treatments, we identified junb as a target of canonical Stat3- mediated Il11 signalling and prove its importance for regenerative processes in zebrafish. Specifically, we identify  a novel function for junba and junbb during regeneration to limit  inflammation and fibrosis, to allow scar-free regeneration.  Notably pharmacological intervention with anti-inflammatory drugs is able to partially restore regeneration in a non-regenerative hyperinflammatory junb doublemutant (junba^-/- x junbb^-/-) underlining the importance of tightly regulated inflammatory processes after tissue damage.

Taken together, our findings advance our understanding of the hierarchy of key regenerative pathways and the molecular mechanisms underlying tissue regeneration to provide potential targets for therapeutic interventions supporting tissue regeneration.