Neutrophils and Asthma

Abstract

Although eosinophilic inflammation is characteristic of asthma pathogenesis, neutrophilic inflammation is also marked, and eosinophils and neutrophils can coexist in some cases. Based on the proportion of sputum cell differentiation, asthma is classified into eosinophilic asthma, neutrophilic asthma, neutrophilic and eosinophilic asthma, and paucigranulocytic asthma. Classification by bronchoalveolar lavage is also performed. Eosinophilic asthma accounts for most severe asthma cases, but neutrophilic asthma or a mixture of the two types can also present a severe phenotype. Biomarkers for the diagnosis of neutrophilic asthma include sputum neutrophils, blood neutrophils, chitinase-3-like protein, and hydrogen sulfide in sputum and serum. Thymic stromal lymphoprotein (TSLP)/T-helper 17 pathways, bacterial colonization/microbiome, neutrophil extracellular traps, and activation of nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 pathways are involved in the pathophysiology of neutrophilic asthma and coexistence of obesity, gastroesophageal reflux disease, and habitual cigarette smoking have been associated with its pathogenesis. Thus, targeting neutrophilic asthma is important. Smoking cessation, neutrophil-targeting treatments, and biologics have been tested as treatments for severe asthma, but most clinical studies have not focused on neutrophilic asthma. Phosphodiesterase inhibitors, anti-TSLP antibodies, azithromycin, and anti-cholinergic agents are promising drugs for neutrophilic asthma. However, clinical research targeting neutrophilic inflammation is required to elucidate the optimal treatment.

Keywords: asthma; biologics; biomarkers; eosinophils; inflammation; neutrophils; treatment.

Figure 1

Pathogenesis of neutrophilic asthma. Several cells, including airway epithelial cells, macrophages, T helper (Th) cells, innate helper 3 cells (ILC3), airway smooth muscle cells (ASMCs), and neutrophils play important roles in the pathogenesis of neutrophilic asthma. Airway epithelial cells, stimulated by air pollution, cigarette smoke, bacterial colonization, virus, and allergens, secrete TSLP, IL-33, and IL-25. TSLP secreted from epithelial cells and inflammatory cells converts Th0 to Th17 cells and subsequently induced neutrophil recruitment via IL-8 and GM-CSF, induced by IL-17 from airway epithelial cells. The IL-17/Th17 axis is involved in bacterial colonization and microbiome associated neutrophilic inflammation in asthma. Obesity and GERD are related to severe, neutrophilic asthma and the IL-17/Th17 axis is involved in these conditions. Neutrophil extracellular trap (NETs) formation, damage-associated molecular patterns (DAMPs), and NLPR3 inflammasome are also involved in the pathogenesis of neutrophil asthma.

Figure 2

Airway remodeling in asthma related to neutrophilic inflammation. Airway remodeling in asthma is a characteristic feature of chronic asthma. LTB4, IL-8, LTB4, and TNF-α are elevated in an asthmatic airway and are related to airway remodeling. LTB4, IL-8, and TNF-α induce airway smooth muscle cell proliferation and migration. IL-8 and IL-17 upregulate MUC5A and MUC5B expression in epithelial cells. Abbreviations: IL, interleukin; LTB4, leukotriene B4, TNF-α; Tumor necrosis factor α, BLT1/2: leukotriene B4 receptor 1/2, IL-17R: IL-17 receptor, TNFR: TNF receptor, ASMCs: airway smooth muscle cells.