ST2-Mediated Neutrophilic Airway Inflammation: A Therapeutic Target for Patients With Uncontrolled Asthma

PURPOSE: Suppression of tumorigenicity 2 (ST2) has been proposed as the receptor contributing to neutrophilic inflammation in patients with type 2-low asthma.

However, the exact role of ST2 in neutrophil activation remains poorly understood.

METHODS: A total of 105 asthmatic patients (classified into 3 groups according to control status: the controlled asthma [CA], partly-controlled asthma [PA], and uncontrolled asthma [UA] groups), and 104 healthy controls were enrolled to compare serum levels of soluble ST2 (sST2) and interleukin (IL)-33.

Moreover, the functions of ST2 in neutrophils and macrophages (Mφ) were evaluated ex vivo and in vivo.

RESULTS: Serum sST2 levels were significantly higher in the UA group than in the CA or PA groups (P < 0.05 for all) with a negative correlation between serum sST2 and forced expiratory volume in 1 second % (r = −0.203, P = 0.038).

Significantly higher expression of ST2 receptors on peripheral neutrophils was noted in the UA group than in the PA or CA groups.

IL-33 exerted its effects on the production of reactive oxygen species, the formation of extracellular traps from neutrophils, and Mφ polarization/activation.

In neutrophilic asthmatic mice, treatment with anti-ST2 antibody significantly suppressed proinflammatory cytokines (tumor necrosis factor-alpha and IL-17A) as well as the numbers of immune cells (neutrophils, Mφ, and group 3 innate lymphoid cells) in the lungs.

CONCLUSIONS: These results suggest that IL-33 induces the activation of neutrophils and Mφ via ST2 receptors, leading to neutrophilic airway inflammation and poor control status of asthma.

ST2 could be a therapeutic target for neutrophilic airway inflammation in patients with UA.