Asthma medication may help reduce platelet destruction in ITP, study finds

Terbutaline, an asthma medication, reduced abnormal immune cell activity linked to platelet destruction in laboratory studies of mouse and patient cells with immune thrombocytopenia (ITP).

The study also found evidence that sympathetic nerves help regulate macrophages, immune cells that can shift between inflammation-promoting and inflammation-reducing states.

“Our work suggests that sympathetic regulation may provide a clue to the [development] of ITP and could represent a potential therapeutic target,” the researchers wrote.

The study, “β2-adrenergic receptor agonist regulates macrophage polarization via HMGB1 in immune thrombocytopenia,” was published in Science China Life Sciences.

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How immune cells contribute to platelet destruction in ITP

In ITP, the immune system produces antibodies that mistakenly target platelets, the cell fragments that help blood clot. These antibodies mark platelets for destruction by macrophages, immune cells found in the spleen, an organ that filters blood. The resulting shortage of platelets increases the risk of bleeding inside or outside the body.

Macrophages can take on different roles. M1 macrophages promote inflammation and help fight infections, while M2 macrophages help reduce inflammation and repair tissues. This process, called macrophage polarization, involves a range of states rather than just two distinct types. In ITP, the balance appears to shift toward the inflammation-promoting M1 state.

Sympathetic nerves are among the factors that help regulate macrophage polarization. These nerves release norepinephrine, a chemical messenger that activates proteins called beta2-adrenergic receptors on macrophages. This signaling can encourage macrophages to take on a less inflammatory state.

A research team in China previously treated ITP mice with bambuterol, a drug that is converted to terbutaline in the body. Terbutaline activates beta2-adrenergic receptors and is used to open the airways in people with asthma. In the mice, bambuterol increased regulatory T cells (Tregs), which help control immune activity, and raised platelet counts.

Building on these findings, the researchers examined macrophages from the spleens of mice with active ITP. Compared with healthy mice, those with ITP had a higher ratio of inflammation-promoting M1 macrophages to inflammation-reducing M2 macrophages. Their macrophages also engulfed more platelets, suggesting a link between this imbalance and increased platelet destruction.

The researchers also found fewer sympathetic nerve fibers in the spleens of ITP mice. When they gave healthy mice a chemical that reduces sympathetic nerve activity, macrophages shifted toward a more inflammatory state, and platelet counts fell. These findings suggested that “sympathetic nerves are capable of regulating macrophage polarization and platelet [destruction] in ITP,” the team noted.

Terbutaline reduces platelet destruction in laboratory experiments

The scientists then grew macrophages from the spleens of ITP mice that had received injections of an antibody targeting platelets.

Treating these macrophages with terbutaline lowered M1 markers and increased M2 markers, while reducing the number of platelets they engulfed. Treatment also lowered levels of two pro-inflammatory signaling proteins, interleukin-1-beta and TNF-alpha, and increased levels of an anti-inflammatory signaling protein, interleukin-10.

To investigate how terbutaline worked, the team studied HMGB1, a DNA-binding protein that promotes M1 macrophage polarization. Experiments showed that suppressing HMGB1 produced some of the same anti-inflammatory effects as terbutaline, while adding HMGB1 reversed some of the drug’s effects.

The study also enrolled 20 adults with steroid-resistant or relapsed ITP, including 10 women. In laboratory experiments involving cells from 10 patients and 10 healthy controls, macrophages from ITP patients had higher levels of M1 markers and lower levels of M2 markers. The medium used to grow the patients’ M1 macrophages had less interleukin-10 and more TNF-alpha than that of healthy controls. Macrophages from ITP patients also showed higher HMGB1 expression.

As in the mouse experiments, terbutaline reduced M1 markers and increased M2 markers. Adding HMGB1 reversed some of these changes.

To explore terbutaline’s effect on macrophages and T cells, the researchers grew M1 and M2 macrophages alongside CD4-positive T cells, which help coordinate immune responses. Terbutaline significantly increased the percentage of Tregs and reduced the Th1/Th2 ratio, indicating a shift in the balance of the immune response.

Lastly, ITP mice treated with bambuterol had a lower M1/M2 ratio in the spleen and higher platelet counts than control mice. Bambuterol also lowered blood levels of interleukin-1-beta and TNF-alpha and increased interleukin-10.

“Collectively, our findings suggest a potential regulatory mechanism underlying macrophage dysfunction in ITP, whereby reduced splenic sympathetic … signaling is involved in the imbalance of macrophage polarization,” the researchers wrote. “Future studies incorporating additional markers or [gene activity] profiling would provide a more complete understanding of macrophage polarization in ITP.”