A Host Lipase Detoxifies Bacterial Lipopolysaccharides in the Liver and Spleen*

Baomei Shao, Mingfang Lu, Steven C. Katz, Alan W. Varley, John Hardwick, Thomas E. Rogers, Noredia Ojogun, Donald C. Rockey, Ronald P. DeMatteo, and Robert S. Munford
From the Departments of Internal Medicine, Microbiology and Pathology, University of Texas Southwestern Medical School, Dallas, Texas 75390-9113 and the Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Much of the inflammatory response of the body to blood borne Gram-negative bacteria occurs in the liver and spleen, the major organs that remove these bacteria and their lipopolysaccharide (endotoxin) from the bloodstream. We show here that Lipopolysaccharide undergoes deacylation in the liver and spleen by acyloxyacyl hydrolase (AOAH), an endogenous lipase that selectively removes the secondary fatty acyl chains that are required for Lipopolysaccharide recognition by its mammalian signaling receptor, MD-2-TLR4. We further show that Kupffer cells produce AOAH and are required for hepatic Lipopolysaccharide deacylation in vivo. AOAH-deficient mice did not deacylate Lipopolysaccharide and, whereas their inflammatory responses to low doses of Lipopolysaccharide were similar to those of wild type mice for 3 days after Lipopolysaccharide challenge, they subsequently developed pronounced hepatosplenomegaly. Providing recombinant AOAH restored Lipopolysaccharide deacylating ability to Aoah-/- mice and prevented Lipopolysaccharide-induced hepatomegaly. AOAH-mediated deacylation is a previously unappreciated mechanism that prevents prolonged inflammatory reactions to Gram-negative bacteria and Lipopolysaccharide in the liver and spleen.