Abstract
Air pollution associated with ozone exposure represents a major inducer of respiratory disease in man. In mice, a single ozone exposure causes lung injury with disruption of the respiratory barrier and inflammation. We investigated the role of interleukin-1 (IL-1)-associated cytokines upon a single ozone exposure (1 ppm for 1 h) using IL-1α-, IL-1β-, and IL-18-deficient mice or an anti-IL-1α neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the alarmin IL-1α after ozone exposure and that the acute respiratory barrier injury and inflammation and airway hyperreactivity are IL-1α-dependent. IL-1α signaling via IL-1R1 depends on the adaptor protein myeloid differentiation factor-88 (MyD88). Importantly, epithelial cell signaling is critical, since deletion of MyD88 in lung type I alveolar epithelial cells reduced ozone-induced inflammation. In addition, intratracheal injection of recombinant rmIL-1α in MyD88acid mice led to reduction of inflammation in comparison with wild type mice treated with rmIL-1α. Therefore, a major part of inflammation is mediated by IL-1α signaling in epithelial cells. In conclusion, the alarmin IL-1α released upon ozone-induced tissue damage and inflammation is mediated by MyD88 signaling in epithelial cells. Therefore, IL-1α may represent a therapeutic target to attenuate ozone-induced lung inflammation and hyperreactivity.
Highlights
Ozone (O3) due to air pollution causes acute and chronic respiratory diseases and exacerbation of allergic asthma [1]
We report that alarmin IL-1α expression in lung upon ozone-induced epithelial cell injury and inflammation is dependent of type 1 alveolar epithelial cells via myeloid differentiation factor-88 (MyD88) signaling
Myeloid differentiation factor-88−/−(33), MyD88flox/flox mice were used to generate MyD88 x Acid/AQP5 cre mice, which lack MyD88 in alveolar epithelial type 1 cells [34] as described [6], IL-1α- and IL-1β-deficient mice were provided by Dr Yoichiro Iwakura [35], IL-18−/− from Jackson laboratory, and C57BL/6 littermate control (WT) mice were used for the study
Summary
Ozone (O3) due to air pollution causes acute and chronic respiratory diseases and exacerbation of allergic asthma [1]. Respiratory exposure to ozone induces airway hyperreactivity in humans and animals, cell death, inflammatory cell recruitment, and emphysema [2], and production of cytokines, including IL-6 [3], IL-33 [4], and chemokines, like CXCL1 [keratinocyte chemoattractant (KC)], MIP-2, and MCP-1 in the lung [5]. The TLR4 ligand hyaluronan released upon ozone exposure may activate TLR4 via MyD88 causing inflammation [9,10,11]. MyD88 is used by the interleukin (IL-1) receptor family, including IL-1R1, IL-18R, IL-33R, and IL-36R activating NF-κB inducing pro-inflammatory cytokines expression [12]. A previous study showed that MyD88 is activated upon ozone exposure resulting in airway hyperreactivity and neutrophilic inflammation [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
