Researchers at the University of Chicago Pritzker School of Molecular Engineering have identified a new form of immune memory involving macrophages, a type of white blood cell. This discovery could lead to innovative methods for controlling macrophage activity in treating infections or autoimmune diseases.
Macrophages adjust their molecular signaling patterns after an infection, which influences their response to subsequent infections and immune signals. This adjustment can result in either tolerance, making them less responsive, or a strengthened immune response. "It turns out that macrophages can turn up or down their responses based on what they’ve been exposed to," said UChicago PME Prof. Savas Tay, senior author of the study.
Traditionally, the innate immune system was believed not to adapt or remember prior stimuli. However, recent studies suggest that macrophages might alter their responses over time. Andrew Wang, a University of Chicago M.D./Ph.D. student and first author of the paper, stated: "Classically, what distinguishes the innate immune response from the adaptive immune response is that it doesn’t adapt; it doesn’t have a memory of prior stimuli."
The research involved testing 80 different conditions using a high-throughput microfluidics platform designed by the team. They found that exposure to inflammatory signals sometimes led to priming effects and other times resulted in tolerance. "Our results really underscored the complexity of immune signaling," said Wang.
The study also revealed that higher doses and longer exposures to pathogens increased tolerance as an adaptation to prevent overactivation of the immune system. Conversely, shorter exposures or lower doses often led to priming.
When examining macrophages from mice with sepsis—a condition characterized by widespread inflammation following severe infection—the researchers noted weaker than usual immune responses. This finding suggests potential treatment avenues for sepsis by modulating macrophage activity.
Further analysis showed changes in macrophage activity linked with shifts in nuclear factor kappa-B (NF-κB) activation and chromatin accessibility. The team developed a machine-learning model predicting how macrophages respond to new inflammatory signals based on previous exposure.
"What we’re beginning to understand is how a pathogen can perturb a macrophage and push it toward a new steady state," Wang explained.
This research was published in Cell Systems on February 11, 2025, under the title “Macrophage memory emerges from coordinated transcription factor and chromatin dynamics.” It was supported by funding from various institutions including the University of Chicago Materials Research Science and Engineering Center and the National Science Foundation.