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Abstract:
The innate immune response is triggered rapidly after injury and its
spatiotemporal dynamics are critical for regeneration; however, many
questions remain about its exact role. Here we show that MyD88, a key
component of the innate immune response, controls not only the
inflammatory but also the fibrotic response during zebrafish cardiac
regeneration. We find in cryoinjured myd88-/- ventricles a significant
reduction in neutrophil and macrophage numbers and the expansion of a
collagen-rich endocardial population. Further analyses reveal
compromised PI3K/AKT pathway activation in the myd88-/- endocardium and
increased myofibroblasts and scarring. Notably, endothelial-specific
overexpression of myd88 reverses these neutrophil, fibrotic and scarring
phenotypes. Mechanistically, we identify the endocardial-derived
chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and
using loss-of-function and gain-of-function tools, we show that it
controls neutrophil recruitment. Altogether, these findings shed light
on the pivotal role of MyD88 in modulating inflammation and fibrosis
during tissue regeneration.
Goumenaki et al. uncover that during zebrafish cardiac regeneration,
MyD88 signaling promotes the inflammatory response to injury and
attenuates the endocardial-mediated fibrotic response.
