Innate immune activation in neutrophilic asthma and bronchiectasis

Abstract

Background: The role of the innate immune system in the pathogenesis of asthma is unclear. Activation of innate immune receptors in response to bacterial lipopolysaccharide, viral infection and particulate matter triggers a pre-programmed inflammatory response, which involves interleukin (IL)8 and neutrophil influx. The inflammatory response in asthma is heterogeneous. Aim: To test the hypothesis that innate immune activation may be a relevant inflammatory mechanism in neutrophilic asthma where IL8 levels are increased. Methods: Induced sputum was obtained from non-smoking adults with asthma (n = 49), healthy controls (n = 13) and a positive reference group with bronchiectasis (n = 9). Subjects with asthma were classified into inflammatory subtypes using induced sputum cell counts. Sputum was examined for mRNA expression of the innate immune receptors toll-like receptor (TLR)2, TLR4 and CD14, and inflammatory cytokines. A separate sputum portion was dispersed and the supernatant assayed for surfactant protein A, IL8, soluble CD14 and endotoxin. Results: Expression of innate immune receptors was increased in subjects with bronchiectasis and neutrophilic asthma compared with other asthma subtypes and controls. Increased expression of the receptors TLR2, TLR4 and CD14, as well as the pro-inflammatory cytokines IL8 and IL1b, was observed. Subjects with neutrophilic asthma had higher airway levels of endotoxin than the other groups studied. Conclusion: There is evidence of activation of the innate immune system in asthma which results in the production of pro-inflammatory cytokines and may contribute to the pathogenesis of neutrophilic asthma.

Systemic upregulation of neutrophil -defensins and serine proteases in neutrophilic asthma

“…Similarities have previously been found between ME/NA and NA in terms of the level of innate immune mediators such as IL-8 in induced sputum. 6 However, our recent sputum gene expression study showed that subjects with ME/NA were predominantly clustered with EA rather than NA. 12 Recent work has shown that corticosteroid treatment can induce a sputum neutrophilia, 13 raising the possibility that ME/NA represents corticosteroid-overtreated EA.…”

“…6 An important aspect of lung innate immune responses is the production of antimicrobial proteins such as the a-and b-defensins. 14 Defensins are small arginine-rich cationic peptides with antimicrobial activity against a broad range of pathogens including bacteria, fungi and some enveloped viruses, and exert this antimicrobial effect through membrane permeabilisation of the microbe.…”

“…34 This is particularly relevant as higher levels of airway endotoxin have been detected in NA. 6 Collectively, the data in this study identify a systemic component to the inflammatory response in NA that is focused on the primary neutrophilic granule and suggest active bone marrow involvement in the pathogenesis of the significant airway inflammatory changes in NA.…”

Assessment of dietary fat intake and innate immune activation as risk factors for impaired lung function

“…Asthma involves a heterogeneous inflammatory response, with activation of both the acquired and the innate immune systems (Simpson et al, 2007). Innate immune activation leads to an IL-8-mediated neutrophilic airway inflammation (Simpson et al, 2007).…”

“…IL-6 is a potent inducer of neutrophil responses, which are closely linked to the development of airflow obstruction (AFO) (Shaw et al, 2007). IL-6 and neutrophil responses are also typical features of innate immune activation, which can be persistently activated in neutrophil mediated airway diseases (Simpson et al, 2007).…”