IL-18 Induces Emphysema and Airway and Vascular Remodeling via IFN-γ, IL-17A, and IL-13

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, alveolar destruction, and airway and vascular remodeling. However, the mechanisms that lead to these diverse alterations have not been defined. Objectives: We hypothesized that IL-18 plays a central role in the pathogenesis of these lesions. Methods: We generated and characterized lung-specific, inducible IL-18 transgenic mice. Measurements and Main Results: Here we demonstrate that the expression of IL-18 in the mature murine lung induces inflammation that is associated with the accumulation of CD4 1 , CD8 1 , CD19 1 , and NK1.1 1 cells; emphysema; mucus metaplasia; airway fibrosis; vascular remodeling; and right ventricle cardiac hypertrophy. We also demonstrate that IL-18 induces type 1, type 2, and type 17 cytokines with IFN-g-inhibiting macrophage, lymphocyte, and eosinophil accumulation while stimulating alveolar destruction and genes associated with cell cytotoxicity and IL-13 and IL-17A inducing mucus metaplasia, airway fibrosis, and vascular remodeling. We also highlight interactions between these responses with IL-18 inducing IL-13 via an IL-17A-dependent mechanism and the type 1 and type17/ type 2 responses counterregulating each another. Conclusions: These studies define the spectrum of inflammatory, parenchymal, airway, and vascular alterations that are induced by pulmonary IL-18; highlight the similarities between these responses and the lesions in COPD; and define the selective roles that type 1, type 2, and type 17 responses play in the generation of IL-18-induced pathologies.Keywords: IL-18; chronic obstructive pulmonary disease; airway fibrosis; mucus metaplasia; vascular remodeling Chronic obstructive pulmonary disease (COPD) encompasses several clinical syndromes, most notably emphysema and chronic bronchitis (1, 2). It is a major unmet medical need in the United States and worldwide where it is the fourth and fifth leading cause of morbidity and mortality, respectively (3, 4). This is caused partly by our limited ability to treat people with COPD and a distinct lack of disease-modifying therapies (4, 5). Tissues from patients with COPD are characterized pathologically by chronic inflammation and varying degrees of emphysematous alveolar destruction, airway remodeling with tissue fibrosis and mucus metaplasia (6, 7), vascular remodeling with intimal hyperplasia, smooth muscle proliferation, and collagen deposition (8, 9). Importantly, a mechanistic construct that adequately accounts for the simultaneous existence of these varied tissue pathologic responses has not been put forth and animal models that simultaneously elicit these varied responses have not been commonly used. In particular, a mechanism that allows tissue destruction (emphysema) to coexist millimeters away from airway and vascular fibrotic responses has not been described (7).Inflammation with infiltrating macrophages, neutrophils, lymphocytes, and occasionally eosinophils is seen throughout the bronchial tree and parenchyma of lung...

Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans

“…Moreover, there was higher expression of il18 in BALB/cJ relative to C57BL/6J mice, both at baseline and after elastase administration. Mice overexpressing either IFN-␥ or IL-18 specifically in the adult lung displayed an emphysema-like phenotype accompanied by high levels of proteases such as MMP-12 and cathepsins in prior studies (40,84). In addition, it was also reported that IL-17A-deficient mice develop less pulmonary inflammation accompanied by a reduction in the severity of emphysema after elastase exposure (43).…”

Sputum mucin 1 is increased during the acute phase of chronic obstructive pulmonary disease exacerbation

“…The increase of sputum MUC1 CT fragment in AECOPD was probably due to detachment of damaged epithelial cells carrying overexpressed MUC1 caused by background chronic inflammation plus a flare up of inflammation in acute exacerbation, since hallmark features of COPD include obstructive bronchiolitis and emphysema parenchymal destruction (21,22). In order to maintain the epithelial integrity, the detachment of damaged cells from the monolayer results from extrusion effects by dedifferentiated ciliated cells (23).…”

Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease

“…These studies were among the first to imply a possible contributory role for inflammasome signaling and IL-1b responses in CS-induced airways inflammation (37). Targeted overexpression of the inflammasome-regulated cytokine, IL-18, in murine lungs resulted in widespread pulmonary inflammation, airway remodeling, and emphysematous lesions, suggesting a role for IL-18 in COPD pathogenesis (38).…”