LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma.

Allergic asthma is a chronic inflammatory disease primarily mediated by Th2 immune mechanisms. Numerous studies have suggested that early life exposure to lipopolysaccharide (LPS) is negatively associated with allergic asthma. One proposed mechanism invokes desensitization of lung epithelial cells by LPS. We report here that acyloxyacyl hydrolase (AOAH), a host lipase that degrades and inactivates LPS, renders mice more susceptible to house dust mite (HDM)-induced allergic asthma. Lung epithelial cells from Aoah(-/-) mice are refractory to HDM stimulation, decreasing dendritic cell activation and Th2 responses. Antibiotic treatment that diminished commensal LPS-producing bacteria normalized Aoah(-/-) responses to HDM, while giving LPS intrarectally ameliorated asthma. Aoah(-/-) mouse feces, plasma, and lungs contained more bioactive LPS than did those of Aoah(+/+) mice. By inactivating commensal LPS, AOAH thus prevents desensitization of lung epithelial cells. An enzyme that prevents severe lung inflammation/injury in Gram-negative bacterial pneumonia has the seemingly paradoxical effect of predisposing to a Th2-mediated airway disease.