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.

Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons.

Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida, trained innate immunity can be modeled in vitro. In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity in vitro, which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.

Increased Plasma Heparanase Activity in COVID-19 Patients.

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.