Acid ceramidase regulates innate immune memory

Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm 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 an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.</p

Acid ceramidase regulates innate immune memory

Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm 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 an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.</p

Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons

Contains fulltext : 227079.pdf (publisher's version ) (Open Access

Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery

In humans, the zinc-dependent histone deacetylases (HDACs) are a family of 11 nonredundant isoforms that catalyze the dynamic reversal of posttranslationally modified acyl-lysine residues back to lysine. At the epigenetic level, HDACs have a critical gene silencing effect, promoting the compaction of histone tails with DNA to prevent transcription. In addition, HDACs deacylate many nonhistone substrates in diverse cellular compartments to profoundly influence protein structure and function. While the action of HDACs is indispensable to normal physiology, their abnormal overexpression is linked to the majority of human diseases. Consequently, the inhibition of HDACs has become a valuable target for therapeutic applications. Numerous potent small molecules are known, of both natural product and synthetic origin, that inhibit HDACs, primarily by reversibly interacting with the zinc cation within the enzyme active site. At the present time, five such HDAC inhibitors have received regulatory approval for the treatment of hematological cancers. This review focuses on the typical zinc-binding groups employed in HDAC inhibitors and the major advances within each class in terms of potency, isoform selectivity, and clinical applications