Acid ceramidase regulates innate immune memory

Innate immune memory, also called "trained immunity," is a metabolically and epigenetically regulated functional state of myeloid cells. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We found that exogenously administered sphingolipids and inhibition of enzymes involved in sphingolipid metabolism modulate trained immunity. In particular, we found that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We discovered that acid ceramidase regulates the expression of genes encoding histone-modifying enzymes, resulting in profound changes in the epigenetic landscape. We confirmed our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal a novel immunomodulatory effect of sphingolipids, provide new insight into the metabolic regulation of trained immunity, and identify acid ceramidase as a therapeutic target to modulate it. ChIP sequencing and RNA sequencing on trained monocytes that are treated with Rapamycin, Ceranib or HKCA