ROLE OF IL-33 IN LUNG THROMBOPOÏESIS DURING AIRWAY INFLAMMATION – INSIDE-LUNGS

To understand IL-33’s effect on platelets, we used several complementary approaches:

1. Animal models: We studied mice in which the IL-33 gene was either inactivated or stimulated to observe its impact on platelet production and function. Live imaging in the lungs allowed us to see how platelet-producing cells fragment and release new platelets into the bloodstream.

2. Biological analyses: We examined the proteins present in platelets and how they change under the influence of IL-33. This helped us understand which platelet functions are affected, including their ability to move, attach to blood vessels, and participate in inflammation.

3. Human genetic studies: We identified and analyzed rare mutations in the IL33 and ST2 genes in patients with low platelet counts. Using computational models and functional analyses, we predicted and tested the impact of these mutations on IL-33 signaling.

4. Multidisciplinary approach: Combining all these methods allowed us to link IL-33, platelet-producing cells, and platelet function in the blood. These approaches were designed to be understandable, reproducible, and directly related to health issues observed in humans.

Our work shows that platelets do not produce IL-33 themselves, but this molecule strongly influences their production and function. The absence of IL-33 changes the protein composition of platelets and reduces their ability to stick and form clots, suggesting that platelet programming begins even before they enter the bloodstream.

We directly observed that megakaryocytes, the cells producing platelets, fragment in the lungs to rapidly release new platelets. IL-33 stimulation accelerates this process, producing larger, more active platelets ready to respond to inflammation.

We identified specific target cells expressing the ST2 receptor, which allows IL-33 to regulate platelet production through rapid pathways, especially under stress or aging conditions.

Finally, studying human variants showed that an IL33 mutation causes a loss of function, and an ST2 mutation alters intracellular signaling. Their co-occurrence in a thrombocytopenic patient suggests these mutations disrupt platelet homeostasis, confirming the importance of the IL-33/ST2 axis in human health.

These results open new perspectives for human health. Understanding IL-33’s role in platelet production and function could lead to targeted treatments for inflammatory and respiratory diseases, such as asthma or COPD, and for platelet disorders.

These studies also identify potential biomarkers to monitor platelet status and the effectiveness of anti-inflammatory treatments. In the long term, they could help design therapies that more precisely and personally regulate platelet production, especially in elderly or vulnerable patients.

Scientifically, our approaches pave the way to study other “alarmin” molecules like IL-33 in regulating blood cells and immune responses. They also lay the foundation for new research on the interactions between local inflammation and systemic hematopoietic responses.

Asthma is an inflammatory disease due to a combination of environmental and genetic factors. Mutations in the interleukin-33 gene are reproducibly associated with the disease. This cytokine has an essential role in every types of asthma. However, the diversity of its target cells and their roles in the disease are not completely understood, especially in severe asthma where type 2 low inflammation is less important. We have preliminary data suggesting that IL-33 can activate a recently discovered population of lung megakaryocyte and that IL-33 affects platelet activation during airway inflammation. Platelets play an active role in the development of asthma and are locally produced in the lung. We hypothesize that IL-33 early release modify lung thrombopoiesis, driving the uncontrolled immune and remodeling responses observed in asthma. We propose to use murine models and cutting edge lung intravital microscopy to decipher the role of IL-33 on megakaryocytes and platelet activation for a deeper understanding of the disease.