Interleukin-1α Mediates Ozone-Induced Myeloid Differentiation Factor-88-Dependent Epithelial Tissue Injury and Inflammation

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-1 alpha-, IL-1 beta-, and IL-18-deficient mice or an anti-IL-1 alpha neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the alarmin IL-1 alpha after ozone exposure and that the acute respiratory barrier injury and inflammation and airway hyperreactivity are IL-1 alpha-dependent. IL-1 alpha 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-1 alpha in MyD88(acid) mice led to reduction of inflammation in comparison with wild type mice treated with rmIL-1 alpha. Therefore, a major part of inflammation is mediated by IL-1 alpha signaling in epithelial cells. In conclusion, the alarmin IL-1 alpha released upon ozone-induced tissue damage and inflammation is mediated by MyD88 signaling in epithelial cells. Therefore, IL-1 alpha may represent a therapeutic target to attenuate ozone-induced lung inflammation and hyperreactivity.