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

Overview

Journal Allergy Asthma Immunol Res

Date 2024 Jan 23

PMID 38262389

Authors

Quang Luu Quoc

Thi Bich Tra Cao

Jae-Hyuk Jang

Yoo Seob Shin

Youngwoo Choi

Hae-Sim Park

Affiliations

Soon will be listed here.

Abstract

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 and .

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

Citing Articles

Next-Generation Therapeutic Approaches for Uncontrolled Asthma: Insights Into the Heterogeneity of Non-Type 2 Inflammation.

Kim S Allergy Asthma Immunol Res. 2024; 16(1):1-5.

PMID: 38262386 PMC: 10823145. DOI: 10.4168/aair.2024.16.1.1.

References

Turan N, van der Veen T, Draijer C, Fattahi F, Ten Hacken N, Timens W . Neutrophilic Asthma Is Associated With Smoking, High Numbers of IRF5+, and Low Numbers of IL10+ Macrophages. Front Allergy. 2022; 2:676930. PMC: 8974785. DOI: 10.3389/falgy.2021.676930. View

Le H, Tran V, Kim W, Kim J, Cho H, Kwon B . IL-33 priming regulates multiple steps of the neutrophil-mediated anti-Candida albicans response by modulating TLR and dectin-1 signals. J Immunol. 2012; 189(1):287-95. DOI: 10.4049/jimmunol.1103564. View

Peden D . The epidemiology and genetics of asthma risk associated with air pollution. J Allergy Clin Immunol. 2005; 115(2):213-9. DOI: 10.1016/j.jaci.2004.12.003. View

Pfirschke C, Engblom C, Gungabeesoon J, Lin Y, Rickelt S, Zilionis R . Tumor-Promoting Ly-6G SiglecF Cells Are Mature and Long-Lived Neutrophils. Cell Rep. 2020; 32(12):108164. PMC: 7508173. DOI: 10.1016/j.celrep.2020.108164. View

Luu Quoc Q, Moon J, Lee D, Ban G, Kim S, Park H . Role of Thymus and Activation-Regulated Chemokine in Allergic Asthma. J Asthma Allergy. 2022; 15:157-167. PMC: 8828566. DOI: 10.2147/JAA.S351720. View

Wang Z, Shi L, Hua S, Qi C, Fang M . IL-33 ameliorates experimental colitis involving regulation of autophagy of macrophages in mice. Cell Biosci. 2019; 9:10. PMC: 6332617. DOI: 10.1186/s13578-019-0271-5. View

Tembhre M, Sriwastva M, Hote M, Srivastava S, Solanki P, Imran S . Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis. Antioxidants (Basel). 2022; 11(12). PMC: 9774908. DOI: 10.3390/antiox11122343. View

OByrne P, Metev H, Puu M, Richter K, Keen C, Uddin M . Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016; 4(10):797-806. DOI: 10.1016/S2213-2600(16)30227-2. View

Jin R, Xu J, Gao Q, Mao X, Yin J, Lu K . IL-33-induced neutrophil extracellular traps degrade fibronectin in a murine model of bronchopulmonary dysplasia. Cell Death Discov. 2020; 6:33. PMC: 7198621. DOI: 10.1038/s41420-020-0267-2. View

10.

Gao P, Tang K, Lu Y, Huang Z, Wang S, Wang M . Pentraxin 3 promotes airway inflammation in experimental asthma. Respir Res. 2020; 21(1):237. PMC: 7493172. DOI: 10.1186/s12931-020-01499-6. View

11.

Choi Y, Kim Y, Lee H, Mun J, Sim S, Lee D . Eosinophil extracellular traps activate type 2 innate lymphoid cells through stimulating airway epithelium in severe asthma. Allergy. 2019; 75(1):95-103. DOI: 10.1111/all.13997. View

12.

Ono Y, Nagai M, Yoshino O, Koga K, Nawaz A, Hatta H . CD11c+ M1-like macrophages (MΦs) but not CD206+ M2-like MΦ are involved in folliculogenesis in mice ovary. Sci Rep. 2018; 8(1):8171. PMC: 5970206. DOI: 10.1038/s41598-018-25837-3. View

13.

Ray A, Kolls J . Neutrophilic Inflammation in Asthma and Association with Disease Severity. Trends Immunol. 2017; 38(12):942-954. PMC: 5711587. DOI: 10.1016/j.it.2017.07.003. View

14.

Esteban-Gorgojo I, Antolin-Amerigo D, Dominguez-Ortega J, Quirce S . Non-eosinophilic asthma: current perspectives. J Asthma Allergy. 2018; 11:267-281. PMC: 6211579. DOI: 10.2147/JAA.S153097. View

15.

Pham D, Ban G, Kim S, Shin Y, Ye Y, Chwae Y . Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma. Clin Exp Allergy. 2016; 47(1):57-70. DOI: 10.1111/cea.12859. View

16.

Peters M, McGrath K, Hawkins G, Hastie A, Levy B, Israel E . Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med. 2016; 4(7):574-584. PMC: 5007068. DOI: 10.1016/S2213-2600(16)30048-0. View

17.

Allinne J, Scott G, Lim W, Birchard D, Erjefalt J, Sanden C . IL-33 blockade affects mediators of persistence and exacerbation in a model of chronic airway inflammation. J Allergy Clin Immunol. 2019; 144(6):1624-1637.e10. DOI: 10.1016/j.jaci.2019.08.039. View

18.

Kang N, Song W . Discovering Biomarkers of Neutrophilic Asthma: A Clinician's Perspective. Allergy Asthma Immunol Res. 2022; 14(1):1-4. PMC: 8724821. DOI: 10.4168/aair.2022.14.1.1. View

19.

Pelaia C, Vatrella A, Crimi C, Gallelli L, Terracciano R, Pelaia G . Clinical relevance of understanding mitogen-activated protein kinases involved in asthma. Expert Rev Respir Med. 2020; 14(5):501-510. DOI: 10.1080/17476348.2020.1735365. View

20.

Busse W, Holgate S, Kerwin E, Chon Y, Feng J, Lin J . Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013; 188(11):1294-302. DOI: 10.1164/rccm.201212-2318OC. View