Biology subjects

Schurich, A.

Publications and source records attributed to Schurich, A..

3 recordsLinked to original sources

bioRxiv2026

Extracellular citrate modulates glutamine metabolism in human macrophages during infection

Citrate is a central metabolite linking tricarboxylic acid (TCA) cycle activity to energy and lipid metabolism and supports the synthesis of inflammatory mediators, including itaconate, in macrophages. While citrate is primarily generated endogenously, extracellular citrate levels are elevated under pathological conditions such as citrate transporter disorder. Cells import extracellular citrate through SLC13 transporters, including the sodium-dependent citrate transporter NaCT (encoded by SLC13A5). However, whether macrophages take up extracellular citrate and how this affects metabolism and function remains unclear. Here, we combined mass spectrometry and tracing approaches to investigate the metabolic fate of citrate in human macrophage cell lines, primary, and iPSC-derived macrophages. We demonstrate that cells take up extracellular citrate, which was enhanced under metabolic stress conditions. Exogenous citrate was not substantially utilized as a carbon source but selectively altered glutamine metabolism and responses to bacterial infection with Salmonella enterica Typhimurium and Legionella pneumophila Corby. Our work identifies extracellular citrate as a context-dependent regulator in macrophages that decouples uptake from metabolic utilization. HighlightsO_LIMacrophages import extracellular citrate via SLC13 transporters C_LIO_LIExtracellular citrate accumulates under hypoxia and inflammatory activation C_LIO_LIExtracellular citrate does not fuel central carbon metabolism in human macrophages C_LIO_LICitrate modulates glutamine immunometabolism and modulates immune responses C_LI eTOC blurbVo{beta}-Willenbockel et al. demonstrate that human macrophages accumulate extracellular citrate without using it as a major carbon source. Instead, citrate modulates glutamine utilization, inflammatory responses, and host-pathogen interactions revealing a context-dependent regulatory role for extracellular metabolites in immune cell function.

cell biology↗

bioRxiv2024

A balanced CAR-T cell metabolism driven by CD28 or 4-1BB co-stimulation correlates with clinical success in lymphoma patients

Chimeric antigen receptor (CAR) T cell therapy has led to unprecedented success in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL). The most common CAR-T cell products currently in the clinic for DLBCL differ in their co-stimulation moiety, containing either CD28 or 4-1BB, which initiate distinct signalling pathways. Previous work has highlighted the importance of T cell metabolism in fuelling anti-cancer function. We have studied the metabolic characteristics induced by CD28 versus 4-1BB co-stimulation in patient CAR-T cells ex vivo. Our data show that in patients, CD28 and 4-1BB drive significantly divergent metabolic profiles. CD28 signalling endows T cells with a preferentially glycolytic metabolism supporting an effector phenotype and increased expansion capacity, while 4-1BB co-stimulation preserves mitochondrial fitness and results in memory-like differentiation. Despite this divergent programming, T cells in patients responding successfully to therapy were metabolically similar, irrespective of co-stimulator, suggesting that efficient fuelling of CAR-T cells in lymphoma requires a balanced metabolism. In contrast, CAR-T cells in non-responders were pushed to their metabolic extremes. One sentence summaryCD28 and 4-1BB signalling drive divergent metabolic profiles in patient CAR-T cells, however patients that respond to therapy have CAR-T cells that maintain metabolic balance.

immunology↗

bioRxiv2019

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation including Natural Killer (NK) cell responses. Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive NK cell dysregulation. In this study we examined the metabolic processes that characterise NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in human cytomegalovirus (HCMV) infected HIV-1 seronegative individuals. However, the bioenergetic advantage of adaptive CD57+NKG2C+ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS) and limited fuel flexibility upon CD16 stimulation. Defective OXPHOS was accompanied by increased mitochondrial depolarisation and structural alterations indicative of mitochondrial dysfunction, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for receptor stimulation was alleviated upon IL-15 pre-treatment enhancing mammalian target of rapamycin complex1 (mTORC1) activity and NK cell functionality in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.

immunology↗