Immune modulation by poly I:C administration promotes heart regeneration via enhancing phagocytic debris clearance and inflammatory resolution in medaka
Unlike humans, zebrafish naturally regenerate their hearts after injury. Comparative analyses in regenerative zebrafish and non-regenerative medaka identified differential immune responses while modulating immune response by poly I:C (dsRNA/TLR3 agonist) administration may promote heart regeneration in medaka despite the unclear underlying mechanism. Through comparative RNA sequencing and examining injured heart tissues, we found that poly I:C triggers early immune activation and phagocytosis-related gene expression, which leads to faster debris clearance and inflammatory resolution in vivo, dynamically comparable to zebrafish. Inhibiting phagocytosis in medaka impeded debris clearance and poly I:C-induced heart regeneration. Furthermore, single-cell transcriptomic profiling identified macrophage subsets preferentially expressed phagocytosis-related genes upon poly I:C stimulation, including granulins. Administration of recombinant Granulin improved animal survival from cardiac injury and enhanced phagocytotic debris clearance, inflammatory resolution, cardiomyocyte proliferation, and scar resolution. These results revealed that boosting immune responses and phagocyte activity may promote cardiac repair and regeneration via Granulin function.