Every day, billions of cells in the human body reach the end of their life and are quietly removed by the immune system. This continuous disposal operation is essential for healthy tissues, but it creates a major metabolic challenge for the cells responsible for the cleanup. Researchers at the VIB-UGent Center for Inflammation Research and Ghent University have discovered that a protein traditionally associated with cellular stress also functions as a cholesterol sensor in a specialized population of immune cells. Their findings, published in Nature Communications, reveal how dendritic cells adapt to the large lipid burden generated by engulfing dying cells and prevent that burden from disrupting immune balance.
The cells at the center of the study are conventional type 1 dendritic cells, or cDC1s. These immune sentinels patrol tissues and continuously engulf dead and damaged cells through a process known as efferocytosis. By clearing cellular remains, cDC1s help prevent the immune system from reacting against the body’s own tissues. At the same time, they process material from the engulfed cells and present selected molecular fragments, known as antigens, to T cells. This allows them to monitor tissues for signs of infection or disease while normally maintaining tolerance to healthy self-components.
Efferocytosis, however, is not simply a matter of collecting cellular waste. Every dying cell contains membranes and intracellular structures rich in lipids, including cholesterol. When a dendritic cell repeatedly consumes this material, it can receive far more cholesterol than it immediately needs. Excess cholesterol is potentially toxic: it can alter membrane properties, interfere with organelle function, trigger inflammatory pathways, and ultimately compromise cell survival. The new study shows that cDC1s possess a specialized mechanism for sensing this metabolic pressure and responding before cholesterol accumulation becomes damaging.
That mechanism depends on IRE1, or inositol-requiring enzyme 1, a protein best known as one of the principal sensors of endoplasmic reticulum stress. The endoplasmic reticulum is the cellular compartment where many proteins are folded and prepared for use. When misfolded proteins accumulate there, IRE1 normally initiates the unfolded protein response, a signaling program that adjusts protein production and activates protective genes. The researchers found that in dendritic cells, IRE1 can also be activated after the cells engulf dying cells and acquire a substantial cholesterol load. In this setting, its activity reflects a metabolic challenge rather than classical protein-folding stress.
“Our findings show that IRE1 is activated when dendritic cells engulf dying cells and take up large amounts of cholesterol,” says Prof. Sophie Janssens of the VIB-UGent Center for Inflammation Research, senior author of the study. “Rather than responding only to classical cellular stress, IRE1 acts as a sensor that helps these immune cells adapt to the metabolic consequences of processing dying cells.” This unexpected role expands the known functions of IRE1 and illustrates how immune cells can connect metabolic information with decisions about survival and immune activity.
The researchers found that IRE1 controls a pathway that promotes cholesterol disposal. A key part of this process involves the regulation of a microRNA, a short RNA molecule that can suppress the production of specific proteins after gene transcription. When IRE1 is activated, it cleaves a microRNA that would otherwise restrain the expression of ABCG1. This protein is a cholesterol transporter located in the cell membrane. ABCG1 helps move surplus cholesterol out of the cell and toward extracellular acceptors, including high-density lipoprotein, or HDL, particles. By relieving microRNA-mediated repression, IRE1 allows dendritic cells to increase their cholesterol-export capacity precisely when it is most needed.
The consequences of removing IRE1 were pronounced. In dendritic cells lacking the protein, cholesterol accumulated intracellularly after the cells engulfed dying material. This excess lipid burden impaired cellular fitness, reduced survival, and weakened functions required for effective immune surveillance. The researchers were able to improve the condition of IRE1-deficient cells by supplying reconstituted HDL particles, which enhance cholesterol removal. This rescue experiment provided direct evidence that disrupted cholesterol handling, rather than an unrelated defect, was a major cause of the cellular dysfunction.
The study also examined what happens at the level of the immune response. Dendritic cells must mature and present antigens efficiently before they can activate T cells. In mice lacking IRE1 specifically in dendritic cells, the immune system was less efficient at activating T cells in response to material derived from dying cells. This finding links the molecular cholesterol-export pathway to a broader biological outcome: the ability of dendritic cells to process self-derived material while regulating immune tolerance and surveillance. If these cells cannot maintain lipid balance, their capacity to communicate with T cells is compromised.
“Our findings place IRE1 at the center of how dendritic cells sense and process dying cells,” says first author Dr. Victor Bosteels of VIB-UGent. “The study uncovers an unexpected connection between cholesterol metabolism and immune tolerance, adding a new layer to our understanding of how the immune system maintains balance.” The work may have implications for diseases in which defective clearance of dying cells, abnormal lipid metabolism, or inappropriate immune activation contribute to pathology, including autoimmune and inflammatory disorders.
The researchers emphasize that the findings are a mechanistic advance rather than an immediate treatment strategy. Nevertheless, identifying IRE1 as a regulator of cholesterol homeostasis in dendritic cells could open new avenues for studying how immune cells respond to chronic lipid stress. Modulating the IRE1–microRNA–ABCG1 pathway, or supporting cholesterol export through HDL-related mechanisms, may eventually help explain why immune regulation fails in some diseases. More broadly, the study shows that proteins classified according to one cellular function can perform highly specialized tasks in distinct immune contexts, revealing how the immune system integrates metabolic signals with the need to maintain tissue-wide homeostasis.
Subject of Research: Cells
Article Title: The unfolded protein sensor IRE1 is essential for homeostatic dendritic cell maturation
News Publication Date: 11 August 2026
Web References: https://doi.org/10.1038/s41467-026-75716-z
References: Nature Communications, article published 16 July 2026; DOI: 10.1038/s41467-026-75716-z
Keywords: IRE1, dendritic cells, cDC1, cholesterol metabolism, ABCG1, HDL, efferocytosis, immune tolerance, antigen presentation, immune homeostasis, cellular stress, inflammation
Tags: balancing immune response and self-tolerancecellular stress proteins in immunitycholesterol sensing mechanisms in immune cellsCholesterol sensor in immune cellsdendritic cell immune regulationefferocytosis and dead cell clearanceimmune cell stress responseimmune system lipid metabolisminflammation and immune homeostasislipid burden management in immune cellsspecialized immune cell functions in tissue healthT cell activation and tolerance
