Neutrophilic Inflammation in Asthma and Association with Disease Severity

Abstract

Asthma is a chronic inflammatory disorder of the airways. While the local infiltration of eosinophils and mast cells, and their role in the disease have long been recognized, neutrophil infiltration has also been assessed in many clinical studies. In these studies, airway neutrophilia was associated with asthma severity. Importantly, neutrophilia also correlates with asthma that is refractory to corticosteroids, the mainstay of asthma treatment. However, it is now increasingly recognized that neutrophils are a heterogeneous population, and a more precise phenotyping of these cells may help delineate different subtypes of asthma. Here, we review current knowledge of the role of neutrophils in asthma and highlight future avenues of research in this field.

Figure 1. Contrasting features of eosinophilic mild asthma and mixed neutrophilic/eosinophilic severe asthma

Eosinophilic allergic asthma is characteristic of 50% of mild asthma. Other features of mild allergic asthma include increased type 2 inflammation in the airways accompanied by elevated serum IgE levels, mast cell activation and attenuation of symptoms by low dose inhaled corticosteroids. In mild allergic asthma, eosinophils typically undergo apoptosis in the presence of corticosteroids. In contrast, neutrophils can be detected in the airways of severe asthmatics, often in conjunction with eosinophils. Neutrophils infiltrate the airways of asthmatics during asthma exacerbations, and have been detected in the airways of individuals who died from an asthma attack. Pathogens, smoking and different co-morbidities can trigger neutrophil recruitment to the airways. The cytokines CXCL8, IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and the leukotriene LTB4 promote neutrophil infiltration of the airways with the neutrophils themselves occasionally being a source of CXCL8 providing a feed-forward loop. While mediators released from neutrophils like reactive oxygen species (ROS) and proteases help in host defense, some of these proteases such as elastase and MMP-9 negatively regulate the levels of TIMP-1 and SLPI creating a protease-antiprotease imbalance, which can promote bronchoconstriction. Increased secretion of TGF-p by neutrophils promotes airway remodeling, a characteristic feature of persistent asthma. Neutrophils are generally resistant to the anti-inflammatory or pro-apoptotic effects of corticosteroids. Resistance to corticosteroid-induced apoptosis is also observed in the case of eosinophils in severe disease. Although neutrophilic airway inflammation is well described in asthmatics, there is insufficient information regarding their phenotype or state of activation or even their inflammatory or suppressive function in different asthmatics, which should be taken into consideration before targeting these cells to alleviate asthma.