A team from the University of Bonn and the Research Center Borstel, Leibniz Lung Center (FZB) has discovered a previously unknown mechanism of action for a synthetic peptide that mitigates excessive inflammatory responses in allergic asthma. This mechanism specifically inhibits a key inflammatory switch in the immune system and opens up new avenues for treating chronic inflammatory diseases. The findings have now been published in the journal Advanced Science.

Chronic inflammation of the airways, such as allergic asthma, results from a complex interplay of various factors. The innate immune system becomes unbalanced and overreacts to environmental stimuli that are actually harmless. The so-called NLRP3 inflammasome plays a central role in this dysregulation. This protein complex acts as a kind of molecular inflammation switch that responds to danger signals and triggers immune responses. When overactivated, this mechanism contributes to the development of chronic—that is, long-term—inflammatory processes. The inflammasome is therefore considered an important therapeutic target for improving the treatment of chronic inflammatory diseases in the future.

A research team from the Research Center Borstel, Leibniz Lung Center (FZB) and the University of Bonn, in collaboration with groups from the University Hospital of Bonn, the University of Graz and Queen's University Belfast, has discovered a new approach to specifically reduce these excessive inflammatory reactions in the human body. The focus is on the synthetic peptide Pep19-2.5. It belongs to the class of membrane-active peptides that can specifically bind to bacterial cell membranes. The researchers demonstrate that Pep19-2.5 can also bind to the membranes of human immune cells. This property makes the peptide particularly interesting for controlling an excessive innate immune response, since a crucial step in inflammasome activation takes place on the inner membranes of immune cells.

As part of the study, the peptide's effects were first investigated in vitro using cell lines and primary human immune cells. The focus was particularly on monocytes and macrophages, which, as cells of the innate immune system, play an important role in immune defense both in the blood and in organs such as the lungs.

The researchers specifically triggered inflammatory reactions using an active substance that, like an ignition key, initiates the activation of the inflammasome within the cell. The complex mechanism of NLRP3 inflammasome activation was examined step by step to identify the peptide's targets. Using highly sensitive biophysical methods, they were able to identify the target structure of the Pep19-2.5 peptide within immune cells—both in models of the immune cell membrane and in living cells—and thereby elucidate how the peptide's effect on the lipid structures in the cell membrane can inhibit inflammasome activation. The scientists demonstrate that this mechanism works not only with the model substance as a trigger but also in experiments with house dust mite extract, which triggers strong inflammatory reactions of the NLRP3 inflammasome in immune cells—reactions that can cause airway inflammation and asthma in people with house dust mite allergies.

In the second step, the team tested the effect in a mouse model of house dust mite asthma. The peptide was administered via the respiratory tract as a nasal spray. The results clearly show that the peptide inhibits the activation of the NLRP3 inflammasome via a mechanism that has not yet been described. Pep19-2.5 specifically binds to a marker lipid within the cell, alters the properties of the surrounding membrane lipids, and thereby influences the transmission of inflammatory signals before the inflammasome is activated. This led to a significantly reduced release of pro-inflammatory mediators in both human immune cells and an animal model. In the animal model, there was also a significantly attenuated inflammatory response in the airways as well as improved lung function.

"Our results show that key inflammatory processes can be specifically influenced via the cell membrane of immune cells. This opens up new possibilities for the development of therapies for chronic inflammatory respiratory diseases," said Prof. Andra Schromm, head of the Immunobiophysics Research Group at the Borstel Research Center, who is a member of the Cluster of Excellence "Precision Medicine in Chronic Inflammation" and the research focus "Kiel Nano, Surface and Interface Science."

The study's findings have significance far beyond their impact on asthma triggered by house dust mites. "The NLRP3 inflammasome plays a role in a whole range of age-related chronic inflammatory diseases, such as cardiovascular diseases, neuroinflammation, and chronic inflammatory bowel diseases. The use of a peptide to regulate the inflammasome represents a completely new pharmacological approach," explains Prof. Günther Weindl of the Institute of Pharmaceutical Sciences at the University of Bonn, who is a member of the Transdisciplinary Research Areas (TRA) "Life \& Health" and "Sustainable Futures." There is a great need for suitable therapeutic compounds. To date, the search for compounds has focused on small synthetic molecules based on the lock-and-key principle. The findings of this study open up an interesting new alternative in the form of this biologically derived peptide.

Source:

Journal reference:

Engelhardt, J., et al. (2026). Membrane‐Active Peptide Protects Against Inflammation by Targeting NLRP3 Activation at the Trans‐Golgi Network. Advanced Science. DOI: 10.1002/advs.76587. https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.76587