Among vertebrates, zebrafish are remarkable animals as they can regenerate their brains. A recurrent topic in this blog is how the inflammatory response modulates the regenerative versus the non-regenerative output after an injury in different contexts. Whereas inflammation appears to have an inhibitory effect on mammalian neural regeneration (by promoting glial scar formation) and limiting cell proliferation, survival and migration), it does not seem to play such negative effect during zebrafish brain regeneration. On the contrary, a paper from the laboratory of Michel Brand reports not only that inflammation is not inhibitory but is required to activate brain regeneration in zebrafish (http://www.ncbi.nlm.nih.gov/pubmed/23138980).
First, the authors observed how after a brain injury there is a fast inflammatory response with an increase in the number of microglia and leukocytes and the expression of the proinflammatory cytokines IL-8, IL-1b and TNF-a. Then, the authors sought to determine whether this inflammatory response activates radial glial cells. What they did was to experimentally dissect the traumatic brain injury from the inflammatory response by injecting zymosan A in order to induce inflammation without injuring. After zymosan A delivery the induced inflammation detected pretty much mimics the inflammatory response after brain injury. Thus, for example, this induced inflammation results also in an increase in radial glial cells proliferation and their posterior neural differentiation. Remarkably, using an anti-inflammatory drug to immunosuppress the zebrafish significantly reduced the proliferation and neurogenetic response in the lesioned brains.
So far, these results indicate that inflammation is implicated in activating proliferation and neurogenesis. Next, the authors carried a transcriptome screen to identify the players in this process. They identified a cysteinyl leukotriene receptor (cysltr1) being induced after brain injury, predominantly in radial glial cells. Leukotrienes are a family of inflammatory mediators produced from arachidonic acid. In the zebrafish brain, the expression of cysltr1 is upregulated after zymosan A injections. Remarkably, the use of an antagonist of cysltr1 reduces radial glial cells proliferation and neurogenesis after injury. In order to better characterize the role of leukotriene signaling in this process they tested the effects of injecting leukotriene C4 (LTC4), a ligand of cysltr1. The injection of LTC4 into a non-injured brain results in a significant increase in reactive proliferation and neurogenesis. Finally, as the adult zebrafish brains are continuously making new neurons the authors wanted to determine if inflammation enhances neurogenesis by amplifying the existing signals in those adult brains or, alternatively, initiates a specific injury-induced program. To answer this question they analyzed the expression of gata3, a gene that is specifically induced after a brain injury but is not detected under homeostatic conditions. Zymosan A injections are sufficient to induce gata3 upregulation and this expression is silenced when zymosan A is injected in immunosuppressed animals. On the other side, LTC4 injections activate also gata3 expression that, again, is silenced when cysltr1 is blocked. Overall, the authors conclude that the inflammatory response, including LTC4 signalling, initiates a specific neurogenesis regeneration program.
In summary, and although there are contradictory studies about the positive and negative effects of acute inflammation on wound healing this study clearly couples the inflammatory response to cell proliferation and neurogenesis in a regeneration-competent model. This may help to better understand the molecular players required for a successful regeneration in zebrafish and, on the other side, it also opens the door to future therapeutic applications in regeneration-non-competent animals.