Spermidine-induced macrophage reprogramming for liver fibrosis treatment

Liver fibrosis can be regarded as an aberrant wound-healing process in response to chronic hepatic injury, which is characterized by extracellular matrix deposition leading to the generation of the fibrous scar and subsequent hepatic dysfunction. Recently, increasing evidence has proved that hepatic macrophages are dominantly involved in the pathogenesis of chronic liver inflammation and have been proposed as potential targets in combatting liver fibrosis. Spermidine, a natural polyamine, has been shown to ameliorate hepatic injury and fibrosis via inducing autophagy to protect hepatocytes. We show here that spermidine improves carbon tetrachloride (CCl4)-induced hepatic injury and subsequent fibrosis through endowing macrophages a stable anti-fibrotic capacity consisting of anti-inflammatory phenotype polarization as well as elevated matrix metalloproteinase expression, which contributes to the normalization of hepatic repair. This stable regulatory phenotype makes it possible to develop the macrophages-based immune therapeutic strategy for liver fibrosis treatment. Adoptive transfer of these spermidine-preprogrammed macrophages to CCl4-induced hepatic injured and fibrosis mice exhibited obvious alleviation in the process of diseases. Mechanistically, in our study, spermidine exerts its effects by modulating mitochondrial homeostasis in macrophages. Through the upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), these macrophages were found to have a higher mitochondrial mass, undergo oxidative phosphorylation (OXPHOS) and active fatty acid metabolism. Hepatic fibrotic mice in which PGC1α was specifically deleted in myeloid cells were less responsive to spermidine treatment. Absence of PGC1α impaired mitochondrial biogenesis and abolished the anti-fibrotic phenotype of macrophages as well as the therapeutic potential of spermidine. Furthermore, we found that the anti-fibrotic functions of macrophages endowed by spermidine required LC3-associated autophagy, which was prevented by its inhibitor 3-MA and chloroquine treatment. Taken together, our studies revealed that for spermidine to confer macrophages an enhanced anti-fibrotic capacity, PGC1α-mediated augmentation of mitochondrial biogenesis and function in macrophages is required. This study also demonstrated a potential application of trained macrophages in the treatment of liver injury and fibrosis