Abstract
Pseudomonas aeruginosa airway infection increases risks of exacerbations and mortality in chronic obstructive pulmonary disease (COPD). We aimed to elucidate the role of IL-17 in the pathogenesis. We examined the expression and influences of IL-23/IL-17A in patients with stable COPD (n = 33) or acute COPD exacerbations with P. aeruginosa infection (n = 34). A mouse model of COPD (C57BL/6) was used to investigate the role of IL-17A in host inflammatory responses against P. aeruginosa infection through the application of IL-17A–neutralizing antibody or recombinant IL-17A. We found that P. aeruginosa infection increased IL-23/17A signaling in lungs of both COPD patients and COPD mouse models. When COPD mouse models were treated with neutralizing antibody targeting IL-17A, P. aeruginosa induced a significantly less polymorphonuclear leukocyte infiltration and less bacterial burden in their lungs compared to those of untreated counterparts. The lung function was also improved by neutralizing antibody. Furthermore, IL-17A-signaling blockade significantly reduced the expression of pro-inflammatory cytokine IL-1β, IL-18, TNF-α, CXCL1, CXCL15 and MMP-9, and increased the expression of anti-inflammatory cytokine IL-10 and IL-1Ra. The application of mouse recombinant IL-17A exacerbated P. aeruginosa-mediated inflammatory responses and pulmonary dysfunction in COPD mouse models. A cytokine protein array revealed that the expression of retinol binding protein 4 (RBP4) was down-regulated by IL-17A, and exogenous RBP4-recombinant protein resulted in a decrease in the severity of P. aeruginosa-induced airway dysfunction. Concurrent application of IL-17A-neutralizing antibody and ciprofloxacin attenuated airway inflammation and ventilation after inoculation of P. aeruginosa in COPD mouse models. Our results revealed that IL-17 plays a detrimental role in the pathogenesis of P. aeruginosa airway infection during acute exacerbations of COPD. Targeting IL-17A is a potential therapeutic strategy in controlling the outcomes of P. aeruginosa infection in COPD patients.
Highlights
Pseudomonas aeruginosa is a common cause of bacterial infection in Chronic Obstructive Lung Disease (COPD), which can be isolated from sputum samples of 4%-15% of adult chronic obstructive pulmonary disease (COPD) patients [1, 2]
We found blockade of IL-17 signaling significantly attenuated the severity of P. aeruginosa airway infection by suppressing infection-induced cytokines, suggesting IL-17A may be used as a target of adjunctive therapy, in combination with antibiotics, to treat acute exacerbations of COPD (AECOPD) patients with P. aeruginosa infection
To determine the role of IL-17A in the airway dysfunction induced by P. aeruginosa infection in COPD mouse models, we investigated the effects of IL-17A activity in PA-COPD mice by application of IL-17A–neutralizing antibody and exogenous mouse rm-IL-17A, respectively
Summary
Pseudomonas aeruginosa is a common cause of bacterial infection in Chronic Obstructive Lung Disease (COPD), which can be isolated from sputum samples of 4%-15% of adult COPD patients [1, 2]. The immune responses to P. aeruginosa infection are not always protective, and an excessive host inflammatory response can cause lung injury [9]. Neutrophils are crucial for the clearance of bacterial pathogens, but persistent neutrophil recruitment and excessive release of proteases from neutrophils, such as neutrophil elastase (NE) and matrix metalloproteinase-9 (MMP-9), leads to excessive extracellular matrix (ECM) degradation and tissue damage [10]. The ability of P. aeruginosa to activate the NLRC4 inflammasome-mediated production of IL-1b and IL-18 is responsible for a substantial amount of the pathology associated with acute pneumonia, and inhibition of IL-1b, caspase-1, IL-1R, and IL-18R limits pathological consequences of infection and improves bacterial clearance [12, 13]. Rapid resolution of P. aeruginosa infection-induced inflammation is important for reducing the lung injuries, which involves the balance of pro- and anti-inflammatory immune responses including the expression of cytokines and chemokines. The IL-17 family of cytokines is one of such group that can influence the balance of immune responses
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