A new study by researchers at Brigham and Women’s Hospital reveals the mechanisms behind severe inflammation in asthma. The findings demonstrate that prostaglandin E2 (PGE2), a naturally occurring chemical in the human body previously thought to inhibit mast cell activation, elicits mast cells to prevent inflammation by creating a molecule called soluble ST2 (sST2), which can mitigate signs and symptoms of asthma by blocking the actions of interleukin 33. Their findings suggest that mast cells are not just drivers of inflammation, but can also mitigate inflammation when PGE2 is present. It also suggests the PEG2 enlists mast cells to suppress the inflammation that leads to asthma exacerbations.
The study is published in Immunity in an article titled, “Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2.”
“Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2,” the researchers wrote. “Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I.”
Using mouse models of airway inflammation, the researchers examined how deficiencies in PGE2, the loss of PGE2 receptors from mast cells, and the absence of ST2 from mast cells impacted the severity of inflammation. They also found that the levels of PGE2 metabolites in the urine correlated strongly with serum sST2 levels in patients with severe asthma and nasal polyps, and that high serum sST2 levels were associated with milder disease and better lung function.
“Through our work, we found that mast cells likely protect against the mechanisms that drive severe inflammation under conditions of normal PGE2 generation,” explained the researchers. “However, when PGE2 isn’t produced sufficiently, which is common in severe asthma and nasal polyposis, the lack of mast cell-derived sST2 contributes to the severity of disease. Our findings suggest a promise in targeting PGE2 with therapeutics to alter the levels of sST2 in patients with severe asthma. They also suggest that antibodies against ST2 and IL-33, currently in clinical trials, may work best in patients with the lowest levels of PGE2 production.”
The researchers now plan to test the hypothesis that PGE2 and sST2 levels can predict the efficacy of new medicines, including monoclonal antibodies, developed for the treatment of severe asthma and nasal polyposis.
