The IL-17 family of cytokines consists of at least six members (IL-17A to -F). IL-17 directly activates epithelial cells leading to the expression of inflammatory mediators and antimicrobial factors. Recent studies showed that IL-17C is expressed by epithelial cells. It was the purpose of this study to examine the expression of IL-17 family members in respiratory epithelial cells during bacterial infection. We show that common bacterial pathogens, such as Pseudomonas aeruginosa and Haemophilus influenzae, and ligands of Toll-like receptors 3 and 5 (flagellin, polyI:C) induced the expression and release of IL-17C in cultured human bronchial epithelial cells (HBECs). The expression of IL-17A, -B, -D, or -E was not induced by bacterial stimuli in HBECs. IL-17C enhanced inflammatory responses of respiratory epithelial cells infected with P. aeruginosa. Furthermore, we demonstrate that cigarette smoke suppressed the expression of IL-17C in HBECs in response to bacterial infection and in vivo in the upper airways of mice colonized with H. influenzae. IL-17C could also be detected in bronchial tissue of subjects with infection-related lung diseases. These data show that IL-17C is involved in the innate immune response of respiratory epithelial cells and is suppressed by cigarette smoke.

In phagocytes, pathogen recognition is followed by Ca(2+) mobilization and NADPH oxidase 2 (NOX2)-mediated "oxidative burst," which involves the rapid production of large amounts of reactive oxygen species (ROS). We showed that ORAI Ca(2+) channels control store-operated Ca(2+) entry, ROS production, and bacterial killing in primary human monocytes. ROS inactivate ORAI channels that lack an ORAI3 subunit. Staphylococcal infection of mice reduced the expression of the gene encoding the redox-sensitive Orai1 and increased the expression of the gene encoding the redox-insensitive Orai3 in the lungs or in bronchoalveolar lavages. A similar switch from ORAI1 to ORAI3 occurred in primary human monocytes exposed to bacterial peptides in culture. These alterations in ORAI1 and ORAI3 abundance shifted the channel assembly toward a more redox-insensitive configuration. Accordingly, silencing ORAI3 increased the redox sensitivity of the channel and enhanced oxidation-induced inhibition of NOX2. We generated a mathematical model that predicted additional features of the Ca(2+)-redox interplay. Our results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses.

Lung epithelial cells are suggested to promote pathogen-induced pulmonary inflammation by the release of chemokines, resulting in enhanced recruitment of circulating leukocytes. Recent studies have shown that the interleukin-17C (IL-17C) regulates innate immune functions of epithelial cells in an autocrine manner. The aim of this study was to investigate the contribution of IL-17C to pulmonary inflammation in a mouse model of acute Pseudomonas aeruginosa pneumonia. Infection with P. aeruginosa resulted in an increased expression of IL-17C in lung tissue of wild-type mice. Numbers of neutrophils and the expression of the neutrophil-recruiting chemokines keratinocyte-derived chemokine and macrophage inflammatory protein 2 were significantly decreased in lungs of IL-17C-deficient (IL-17C) mice infected with P. aeruginosa at 24 h. Systemic concentrations of interleukin-6 (IL-6) were significantly decreased in infected IL-17C mice at 24 h and the survival of IL-17C mice was significantly increased at 48 h. The expression of IL-17C was reduced in infected mice deficient for interleukin-17A (IL-17A), whereas pulmonary concentrations of IL-17A were not affected by the deficiency for IL-17C. Stimulation of primary alveolar epithelial cells with IL-17A resulted in a significantly increased expression of IL-17C in vitro. Our data suggest that IL-17A-mediated expression of epithelial IL-17C amplifies the release of chemokines by epithelial cells and thereby contributes to the recruitment of neutrophils and systemic inflammation during acute P. aeruginosa pneumonia.

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BackgroundBacterial colonization and recurrent infections of the respiratory tract contribute to the progression of chronic obstructive pulmonary disease (COPD). There is evidence that exacerbations of COPD are provoked by new bacterial strains acquired from the environment. Using a murine model of colonization, we examined whether chronic exposure to cigarette smoke (CS) promotes nasopharyngeal colonization with typical lung pathogens and whether colonization is linked to inflammation in the respiratory tract.MethodsC57BL/6 N mice were chronically exposed to CS. The upper airways of mice were colonized with nontypeable Haemophilus influenzae (NTHi) or Streptococcus pneumoniae. Bacterial colonization was determined in the upper respiratory tract and lung tissue. Inflammatory cells and cytokines were determined in lavage fluids. RT-PCR was performed for inflammatory mediators.ResultsChronic CS exposure resulted in significantly increased numbers of viable NTHi in the upper airways, whereas NTHi only marginally colonized air-exposed mice. Colonization with S. pneumoniae was enhanced in the upper respiratory tract of CS-exposed mice and was accompanied by increased translocation of S. pneumoniae into the lung. Bacterial colonization levels were associated with increased concentrations of inflammatory mediators and the number of immune cells in lavage fluids of the upper respiratory tract and the lung. Phagocytosis activity was reduced in whole blood granulocytes and monocytes of CS-exposed mice.ConclusionsThese findings demonstrate that exposure to CS impacts the ability of the host to control bacterial colonization of the upper airways, resulting in enhanced inflammation and susceptibility of the host to pathogens migrating into the lung.