Biology subjects

Siller, A.

Publications and source records attributed to Siller, A..

3 recordsLinked to original sources

bioRxiv2024

Reorganization of innate immune cell lipid profiles by bioinspired meroterpenoids to limit inflammation

Lipidomics-guided screening of unexplored chemical space in natural products provides access to small molecules capable of modifying cellular lipid profiles on a global scale. Here, we show that the meroterpenoid cyclosmenospongine from Spongia sp. shapes the lipid profile of immune cells, favoring anti-inflammatory and pro-resolving over pro-inflammatory lipid mediators. Structural variation revealed derivatives that inhibit leukotriene biosynthesis to varying extents while differentially upregulating pro-resolving lipid mediators, epoxyeicosatrienoic acids, endocannabinoids, and sphingosine-1-phosphate, along with other mediators, both in resting and activated innate immune cells in vitro and in self-resolving murine peritonitis in vivo. Mechanistically, meroterpenoids target 5-lipoxygenase or 5-lipoxygenase-activating protein, promote the translocation of 15-lipoxygenase-1 to cytoplasmatic sites, and inhibit monoacylglycerol lipase. They also redirect arachidonic acid (AA) from neutral lipids to specific phospholipids, while increasing the total concentration of free AA. Furthermore, meroterpenoids reprogram lipid metabolism in immune cells, decreasing the levels of neutral lipids, triacylglycerols, and cholesteryl esters. This shift correlates with a reduced capacity for leukotriene biosynthesis and is mimicked by the inhibition of sterol-O-acyltransferase and diacylglycerol acyltransferase-1/2. In conclusion, specific meroterpenoids exert anti-inflammatory effects by intervening in lipid mediator biosynthesis, prompting structure-controlled switches in lipid mediator classes, among others, through an unexpected link between lipogenesis and inflammation.

pharmacology and toxicology↗

bioRxiv2023

13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation

Naive T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start proliferation and generation of effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells. Here we used 13C metabolomics and transcriptomics to study the metabolic dynamics of CD8+ T cells in their complete course of differentiation from naive over stem-like memory to effector cells. The quiescence of naive T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naive T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of T cell regulatory genes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which paradoxically was not linked to changes in mitochondrial abundance. We further investigated the metabolic phenotype of exhausted T cells, finding that decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of suppressive and quiescence-associated genes, including TXNIP and KLF2. Thus, these results identify multiple features critical for the metabolic reprogramming that supports quiescence, proliferation and effector function of CD8+ T cells during differentiation. Further, an impairment of the same processes in exhaustion suggests that targeting these control points may be useful for both modulation of differentiation and prevention of exhaustion.

immunology↗

bioRxiv2021

Alternative splicing of auxiliary β2-subunits stabilizes Cav2.3 Ca2+ channel activity in continuously active midbrain dopamine neurons

In dopaminergic (DA) substantia nigra (SN) neurons Cav2.3 R-type Ca2+-currents contribute to somatodendritic Ca2+-oscillations. These may contribute to the selective degeneration of these neurons in Parkinsons disease (PD) since Cav2.3-knockout is neuroprotective in a PD mouse model. However, the typical Cav2.3 gating would predict complete channel inactivation during SN DA neuronal firing. Here we show that in tsA-201-cells the membrane-anchored {beta}2-splice variants {beta}2a and {beta}2e stabilize Cav2.3 gating properties allowing sustained Cav2.3 availability during simulated pacemaking and enhanced Ca2+-currents during bursts. We confirmed the expression of {beta}2a and {beta}2e-subunits in the SN and identified SN DA neurons. Patch-clamp recordings of SN DA neurons in mouse brain slices revealed R-type Ca2+-currents similar to {beta}2a- or {beta}2e-stabilized Cav2.3-currents and recordings in cultured murine DA neurons confirmed their activity during pacemaking. Taken together, our data support an important (patho)physiological role of {beta}-subunit alternative splicing for Cav2.3 Ca2+-signaling in highly vulnerable SN DA neurons.

neuroscience↗