Biology subjects

Hochrein, S. M.

Publications and source records attributed to Hochrein, S. M..

4 recordsLinked to original sources

bioRxiv2025

Glucose Metabolism Controls Oxidative Burst and Lipid Mediator Production in Neutrophils upon Microbial Challenge

Neutrophils are frontline responders against bacterial and fungal pathogens, requiring rapid energy and biosynthetic precursors to mount effective antimicrobial responses. To meet these demands, they primarily rely on aerobic glycolysis, making glucose uptake essential. Murine and human neutrophils express the glucose transporters GLUT1 and GLUT3; however, their specific roles in neutrophil immunobiology have not yet been fully elucidated. Here, we show that neutrophilic immune responses to Candida albicans and Staphylococcus aureus critically depend on GLUT1/3-dependent glucose uptake and glycolysis. Combined deletion of GLUT1 and GLUT3 almost completely abolished glucose uptake and aerobic glycolysis in murine neutrophils, yet did not impair granulopoiesis, indicating that homeostatic neutrophil development is largely independent of extracellular glucose. By contrast, during microbial challenge, loss of GLUT1/3 severely compromised NADPH-dependent ROS production, oxidative burst and cyclooxygenase-derived lipid mediator (LM) biosynthesis, demonstrating that glucose uptake via GLUT1/3 controls inflammatory effector functions of neutrophils. Moreover, genetic and pharmacologic inhibition of GLUT1/3-mediated glucose utilization reprograms neutrophil metabolism and LM biosynthesis toward an immunomodulatory phenotype. These findings identify a conserved nutrient-sensing metabolic checkpoint that governs neutrophil reprogramming and highlight novel opportunities for therapeutic immunomodulation.

immunology↗

bioRxiv2025

Tafazzin-Mediated Cardiolipin Remodeling Controls Metabolic Stress Response and Effector Function of Inflammatory T Cells

Clonal expansion and effector differentiation of T cells require extensive metabolic reprogramming. This includes the restructuring of the inner mitochondrial membrane (IMM) to enhance respiration by increasing chemiosmotic coupling efficiency. Cardiolipin, a unique phospholipid that is exclusively synthesized and localized in the IMM, modulates the biophysical properties of the electron transport chain (ETC) in tissues with high energy demands, such as cardiomyocytes and skeletal muscle. However, it remains unclear whether cardiolipin is also important for metabolic remodeling during T helper (Th) cell differentiation. In this study, we show that cardiolipin transacylation, catalyzed by the enzyme Tafazzin, supports the clonal expansion and effector function of inflammatory Th1 and Th17 cells in vitro and in models of autoimmune colitis and encephalomyelitis. At the molecular level, we demonstrate that loss of Tafazzin-mediated cardiolipin maturation induces a metabolic and transcriptional stress response in Th cells to compensate for impaired coupling efficiency of the ETC complexes and disrupted cellular redox homeostasis. However, the genetic program that restores cellular homeostasis and mitigates oxidative stress concurrently impairs the effector functions of inflammatory T cells, such as cytokine production. Our findings also provide insights into the complex clinical manifestation of patients with Barth syndrome (BTHS) caused by mutations in the human TAFAZZIN gene. BTHS is characterized by cardiac and skeletal myopathy as well as neutropenia and an increased susceptibility to infections. Although the molecular basis of the immunodeficiency remains poorly understood, our findings suggest that impaired Th cell function contributes to the immunopathology observed in BTHS patients.

immunology↗

bioRxiv2025

CD8+ T cells regulate the bioenergetic reprogramming of lymphoid organs and the heart during viral infection

The activation of the immune system is a bioenergetically-costly process1. Yet, essential bodily functions require a continuous energy supply, imposing energy constraints and trade-offs between competing processes2. Our understanding of the underlying bioenergetic adaptations reconciling rapid immune activation with other vital processes remains scarce. 3-6 Here, by using experimental models of viral infections, we identified an unexpected CD8+ T cell-driven redistribution of energy substrates between lymphoid organs and the heart. Viral infection promoted systemic hypoglycaemia and ketogenesis, together with systemic reallocation of energy substrates. Across organs analysed, secondary lymphoid organs and the heart showed the most dramatic changes. The former increased glucose uptake and oxidation while the heart showed the opposite, switching to preferential fatty acid utilization. These bioenergetic adaptations were absent in infected mice lacking CD8+ T cells or with T cells lacking the glucose transporter GLUT1. Pharmacological inhibition of fatty acid oxidation forced a systemic switch to glucose oxidation. This was associated with metabolic decompensation, reduced cardiac energetics, left ventricular stress, and mortality in otherwise nonlethal viral infections. Our results reveal how the energetic cost of immune cell activation imposes bioenergetic adaptations on non-lymphoid organs, posing a major challenge for the heart by completely relying on fatty acids.

immunology↗

bioRxiv2023

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

Functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation of hypoxia inducible factor 1 alpha (HIF-1) in Tpex cells. HIF-1 mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.

immunology↗