Pinelopi Goumenaki and colleagues at the Max Planck Institute for Heart and Lung Research uncovered that during zebrafish cardiac regeneration, MyD88 signaling promotes the inflammatory response to injury and also attenuates the endocardial-mediated fibrotic response. MyD88 is an essential adapter protein mediating innate immune response. Although, a comprehensive understanding of its role in cardiac repair and regeneration remains elusive, with studies reporting conflicting results.
In their study, Goumenaki and colleagues use newly generated genetic tools and transcriptomic profiling to investigate the role of MyD88 signaling during zebrafish cardiac regeneration at several stages and across different cell types. They 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. Remarkably, endothelial-specific overexpression of MyD88 reversed the observed neutrophil reduction, fibrosis, and scarring.
Mechanistically, they identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss- and gain-of-function tools, show that it controls neutrophil recruitment. Overall, their findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration.
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