Title | The Effects of IFN-λ on Epithelial Barrier Function Contribute to Klebsiella pneumoniae ST258 Pneumonia. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Ahn D, Wickersham M, Riquelme S, Prince A |
Journal | Am J Respir Cell Mol Biol |
Volume | 60 |
Issue | 2 |
Pagination | 158-166 |
Date Published | 2019 02 |
ISSN | 1535-4989 |
Abstract | IFN-λ and IL-22, cytokines that share the coreceptor IL-10RB, are both induced over the course of Klebsiella pneumoniae ST258 (KP35) pneumonia. IL-22 is known to protect mucosal barriers, whereas the effects of IFN-λ on the mucosa are not established. We postulated that IFN-λ plays a role in regulating the airway epithelial barrier to facilitate cellular trafficking to the site of infection. In response to IFN-λ, the transmigration of neutrophils across a polarized monolayer of airway epithelial cells was increased, consistent with diminished epithelial integrity. KP35 infection increased epithelial permeability, and pretreatment with IFN-λ amplified this effect and facilitated bacterial transmigration. These effects of IFN-λ were confirmed in vivo, in that mice lacking the receptor for IFN-λ (Ifnlr1) were protected from bacteremia in a murine model of KP35 pneumonia. Conversely, the integrity of the epithelial barrier was protected by IL-22, with subsequent impairment of neutrophil and bacterial transmigration in vitro. Maximal expression of IL-22 in vivo was observed later in the course of infection than IFN-λ production, with high levels of IL-22 produced by recruited immune cells at 48 hours, consistent with a role in epithelial barrier recovery. The divergent and opposing expression of these two related cytokines suggests a regulated interaction in the host response to KP35 infection. A major physiological effect of IFN-λ signaling is a decrease in epithelial barrier integrity, which facilitates immune cell recruitment but also enables K. pneumoniae invasion. |
DOI | 10.1165/rcmb.2018-0021OC |
Alternate Journal | Am. J. Respir. Cell Mol. Biol. |
PubMed ID | 30183325 |
PubMed Central ID | PMC6376406 |
Grant List | K08 HL138289 / HL / NHLBI NIH HHS / United States P30 CA013696 / CA / NCI NIH HHS / United States R35 HL135800 / HL / NHLBI NIH HHS / United States S10 RR027050 / RR / NCRR NIH HHS / United States |
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