IL-17C Is a Mediator of Respiratory Epithelial Innate Immune Response

Abstract

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.

Combined exposure to bacteria and cigarette smoke resembles characteristic phenotypes of human COPD in a murine disease model

“…Interestingly, the bacterial exposure was necessary for the induction of IL-17A, which appeared to be downregulated in the CS exposure group. The IL-17 group of cytokines is considered as one key factor in the development of inflammatory airway disease (Pfeifer et al, 2013).…”

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

“…Similarly, oral administration of flagellin with the trivalent inactivated influenza vaccine was critically important for antibody production, where titers were significantly reduced in TLR5-deficient mice (34). Besides promoting antibody production, flagellin is important for the maturation of lung dendritic cells (14), inhibition of epithelial apoptosis (44), production of IL-17C cells (36), and induction of cathelicidindependent antimicrobial responses (49), all of which coincide with the essential nature of flagellin's mucosal adjuvant activity. It is noteworthy that flagellin was found to be very effective in activating neonatal lung antigen-presenting cells (40).…”

Moxifloxacin modulates inflammation during murine pneumonia

“…It seems to be reasonable that moxifloxacin directly effects the activation of immune cells (e.g. alveolar macrophages) by bacterial pathogens in the infected lungs as observed in the mentioned in vitro studies, since IL-17A is expressed by immune cells and not by epithelial cells [29] and macrophages are a main source of IL-1β during acute infection of the lung [25]. The finding that treatment with moxifloxacin resulted in reduced IL-1β protein concentrations but in increased mRNA transcription in the lungs of mice infected with viable bacteria whereas KC transcription and protein concentrations were reduced in lungs of moxifloxacin-treated mice suggests that moxifloxacin modulates inflammation at different levels.…”