When interleukin-33 protects and when it becomes harmful
In a review article, Dr. Sebastian Serve and Prof. Max Löhning of the German Rheumatology Research Center (DRFZ), a Leibniz Institute, and Charité – Universitätsmedizin Berlin explain why the body’s own alarm signal, interleukin-33 (IL-33) protects against infections and promotes tissue healing in some situations, but under other circumstances promotes diseases such as allergies, chronic inflammation, and tumor growth. According to the authors, the key factors are the quantity, location, and timing of IL-33 release, as well as the cells that detect this signal. Based on these findings, the authors conclude that future therapies targeting this signaling molecule could be more precisely tailored. The study was published in the journal Nature Reviews Immunology.
IL-33 is produced primarily in the skin, lungs, intestines, and blood vessels and is stored in the cell nucleus. When these cells are damaged, IL-33 is released and alerts the immune system via its receptor. IL-33 is a particularly potent signal: after its release, enzymes from inflammatory cells can modify it in such a way that its effect is up to thirty times stronger. To prevent any harm from resulting, its release and effect are strictly regulated by biological mechanisms.
The authors describe how IL-33 can have opposing effects. In tumors, it activates the immune system’s killer cells, but it also promotes cells that suppress the immune response. It acts in a similarly dual role in viral infections, rheumatic diseases, and chronic inflammatory bowel diseases.
The authors provide an explanatory framework for these contrasting effects: It depends on which cells carry the receptor for the alarm signal. Immune cells that suppress inflammation and repair tissue carry it permanently, thereby capturing small amounts of the alarm signal and using it to promote their activity. Other immune cells, which fight viruses and tumor cells but can also damage healthy tissue in the process, express it only temporarily and at a lower density. Therefore, larger amounts of the alarm signal are required to activate them. Many of the contradictory findings in the literature can be interpreted in this way: They do not describe the same process with different outcomes, but rather different cells, tissues, and time points.
“IL-33 is neither a strictly inflammatory nor a strictly healing signal,” explain the authors of the review article. “Whether it is beneficial or harmful depends on how much of it is released, in which tissue this occurs, and which immune cells are present at the site and express the receptor. Therefore, in many diseases, it is not enough to simply turn the signal on or off.”
This has direct implications for new therapies. Several antibodies targeting IL-33 or its receptor are currently being tested in clinical trials; the results vary depending on the disease and the study. The authors see two possible reasons for this: The approaches used so far inhibit the signaling pathway throughout the entire body, thereby suppressing both disease-promoting and protective effects at the same time. In addition, the timing of treatment could be crucial. While inhibition may be beneficial during harmful inflammation, the same treatment could impair healing during the transition to necessary tissue repair.
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Figure: Different regulation of the IL-33 receptor ST2 on cells of type 1 (left) and type 2 immunity (right). Depending on the immune cell type, the expression of the IL-33 receptor ST2 is regulated differently. As a result, IL-33 can have distinct effects in different immune responses — for example, promoting or limiting inflammation. (Figure 3 of the article reproduced with permission from Springer Nature).
