Dysregulation in lung immunity - the protective and pathologic Th17 response in infection

Abstract

Th17 cytokines can play both protective and pathologic roles in the airways. An emerging theme in Th17 cytokine biology is that these responses can mediate tissue pathology when downstream effector cells are dysfunctional, such as neutrophils lacking functional NADPH oxidase in the case of chronic granulomatous disease, or epithelial cells lacking appropriate ion transport as in the case of cystic fibrosis. In this Mini-Review we highlight recent advances in the protective and pathologic roles of Th17 cytokines in the context of infection at the pulmonary barrier.

Keywords: Animal models; CD4 T cells; Cellular immunology; Cytokines; Lung inflammation.

Figure 1. A model of protective versus pathologic Type 17 Immune responses in the lung

Healthy bronchial epithelium can be exposed to pathogens, and intra-epithelial antigen presenting cells can present pathogenic antigens to T cells in both the bronchial submucosa and the lymph nodes, thereby activating IL-17 producing T cells. Cytokines produced by antigen presenting cells can also activate innate cells such as γδ T cells and other cells to produce Th17 cytokines. IL-17 and other cytokines such as TNF-α and IL-22 stimulate production of chemokines to recruit neutrophils to the site of infection. Neutrophils then participate in pathogen killing through multiple processes which include engulfment into phagolysosomes and production of reactive oxygen species in part by the enzyme NADPH. In cystic fibrosis, there is reduced chloride and bicarbonate secretion as well as excessive mucous production resulting in bronchial epithelial surfaces which are coated with inspissated mucous and dysfunctional cilia, creating an ideal environment for pathogen colonization. Chronic pathogen exposure can lead to chronic Th17 cell activation and augmented neutrophil infiltration which generate matrix metalloproteinases (MMPs) and and airway damage. In chronic granulomatous disease, there is a defect in NADPH function which results in phagocytosis of pathogens without effective pathogen killing, causing chronic inflammation by accumulation of dysfunctional neutrophils and ultimately granuloma formation. When the bronchial epithelium is exposed to cigarette smoke antigen, which contains the ligands for the aryl hydrocarbon receptor (Ahr), the activation of Ahr in Th17 cells enhances Th17 cytokine production, leading to chronic inflammation and ultimately may contribute to pathogenesis in chronic obstructive pulmonary disease.