microRNA-252 and FoxO regulate inflammaging through dual inhibition on Dawdle/Acticin of TGF-β pathway in Drosophila

Innate immunity is a highly reactive response aiming at clearing pathogens. Abnormal induction of innate immune genes can lead to deleterious consequences to the host. However, little is known about the intrinsic signaling pathway that prohibits constitutive activation of innate immunity. Here using fruit flies, we profile the microRNA targetomes in young and aged animals. We demonstrate FoxO, and miR-252 inhibit spontaneous induction of innate immunity by repressing Daw. We further determine the signaling cascade by which Daw causes the reduction of Atg8a-mediated selective autophagy on kenny protein, which in turn activates Relish protein and consequential upregulation of innate immune genes. Finally, while aging leads to a decline in FOXO signaling activity concomitant with a progressive induction of innate immune genes, transgenic increase of FoxO, miR-252, and Atg8a in wild-type Drosophila promotes longevity and mitigates the expression of age-onset innate immune genes. Together, we propose that FoxO and miR-252 define a pro-survival mechanism by inhibiting constitutive innate immunity. Find new miRNA-mRNA aging regulator by performing 3d- and 30d-old adult fly RipSeq, explore their mechanism by comparing transcriptome differences between WT and mutant flies, analyze their changes with age using RNA-sequencing data performed at 3d, 15d, 30d and 45d age of WT flies.