Exposure to “Danger Signals” Can Prime the Innate Immune System Into a Long-Term Inflammatory State

When thinking about the immune system, most people think about B and T cells and how they can be trained to recognize pathogens, preventing re-infections. Besides this “adaptive” immune system, we also have an “innate” immune system which acts as first line defense against e.g. bacteria and viruses. The textbook view is that the innate immune system is non-specific so that it’s response always follows the same pattern, even for recurring infections. However, research published today in Stem Cell Reports provides evidence that brief exposure to certain “danger signals” can prime the body’s innate immune system into a long-term hyperreactive and inflammatory state termed “trained innate immunity.” In this process, not only the white blood cells, which are the "work horses” of the innate immune system, but also the long-lived blood stem cells can be trained, generating a long-lasting hyperreactive and inflammatory state. This mechanism can help the body fight infections and prevent their recurrence, but it can also increase the risk of certain cardiovascular disease, in which the innate immune cells actually contribute to disease pathophysiology. To date, most of our knowledge on trained innate immunity comes from animal models and it is not clear if the human innate immune system reacts in the same way as those models.  

To test this, PhD student Daniela Flores-Gomez from the team of Niels Riksen and Siroon Bekkering at Radboud University Medical Center, Netherlands, isolated blood stem cells and white blood cells from human bone marrow and exposed them to the protein IL-1beta, which is one of the main inducers of trained immunity in mice. Just like their mouse counterparts, the human blood stem cells divided more and made more innate white blood cells when stimulated with IL-1beta. Further, the trained white blood cells were hyperreactive, meaning that they produced more inflammatory proteins and stuck more to blood vessels. Interestingly, IL-1beta levels are elevated in patients after heart attack and these patients have an increased risk of developing atherosclerosis. This might be explained by a trained, hyperreactive immune system with stickier, plaque-forming white blood cells. A fat and sugar-rich diet might worsen this effect, as it promotes trained immunity through IL-1beta signalling in lab animals. 

This data shows that trained immunity in humans and lab animals follows the same principles and opens up new avenues for studying trained immunity and its connection to cardiovascular disease and other diseases linked to hyperinflammation.  

Reference: Flores-Gomez D, Hobo W, Ens D van, et al. Interleukin-1β induces trained innate immunity in human hematopoietic progenitor cells in vitro. Stem Cell Rep. 2024. doi: 10.1016/j.stemcr.2024.09.004

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