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Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures ("tolerant"), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah-/- AMs were less responsive to LPS stimulation and less phagocytic than were Aoah+/+ AMs. Upon innate stimulation in the airways, Aoah-/- mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah-/- mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized ("tolerized") AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah-/- AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah-/- AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung. Author summary: AOAH is the host lipase that degrades and inactivates Gram-negative bacterial lipopolysaccharides (LPSs). AOAH is required for recovery from LPS-induced macrophage tolerance. Expressed in the gut, AOAH inactivates microbiota-derived LPS. In this study we found that AOAH-deficient mice were less able to contain pulmonary Pseudomonas aeruginosa infection than were control wildtype mice. Alveolar macrophages (AMs) from Aoah-/- mice were hypo-responsive to innate stimulation and they had reduced phagocytic activity. In addition, Aoah-/- AMs had metabolic changes characteristic of tolerant macrophages as well as increased cell-surface expression of MHC II and co-stimulatory molecules, findings suggesting that they had been stimulated in situ. Treating Aoah-/- mice with p.o. neomycin normalized AMs' innate responsiveness while intrarectal LPS administration tolerized AMs. We conclude that AOAH regulates pulmonary mucosal immunity in part by inactivating LPS in the gut. This study sheds light on a previously unappreciated mechanism that regulates pulmonary immune defense via the gut-lung axis. [ABSTRACT FROM AUTHOR]