Deacylation of structurally diverse lipopolysaccharides by human acyloxyacyl hydrolase.

Erwin, Alice L.; Munford, Robert S.

doi:10.1016/s0021-9258(17)46242-9

Cited by 65 publications

(15 citation statements)

References 47 publications

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“…A second example of differences in endotoxin activity as detected by different assays is that occurring as a consequence of the enzymatic modification of endotoxin. The neutrophil enzyme acyloxyacyl hydrolase, for example, leads to a selective deacylation by removing the secondary (acyloxyacyl-linked) acyl chains of lipid A but not the glucosamine-linked 3-hydroxyacyl chains (94), which results in a 100-fold reduction in dermal Shwartzman response but only a 10-fold reduction in the reactivity in the LAL assay (251).…”

Section: Comparison With Other Bioassaysmentioning

confidence: 99%

Endotoxemia: methods of detection and clinical correlates

1995

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As an assay for endotoxin, the Limulus amebocyte lysate assay has several desirable properties: sensitivity, specificity, and potential for adaptation to a quantitative format. Several modifications have been developed to enhance its potential for clinical application. The modifications that allow quantitative measurement of endotoxin and also improve its application to blood samples are described in this review. In fluids other than blood, the detection of endotoxin with the Limulus amebocyte lysate assay can be used as an aid to identify the presence of gram-negative bacteria, and the assay has established utility. With blood, however, there are a range of factors that interfere with the detection of endotoxemia and there are disparate views with respect to the diagnostic and prognostic significance of the test results. In general, the clinical significance of the finding of endotoxemia broadly parallels the frequency and importance of gram-negative sepsis in the patient groups studied and a decline in endotoxin levels accompanies clinical improvement. However, with therapies designed to reduce levels of endotoxin, or to antagonize its effects, it is unclear whether clinical improvement occurs as a consequence of changes in the levels of endotoxemia.

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Section: Comparison With Other Bioassaysmentioning

confidence: 99%

Endotoxemia: methods of detection and clinical correlates

1995

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“…To find out if the enzyme can deacylate oxPLs, we incubated PGPC and POVPC with purified recombinant human AOAH (rhAOAH) for 2 or 4 hr. Analysis using LC-MS showed that AOAH could remove the sn-2 oxidized fatty acyl chain and sn-1 palmitate from both PGPC and POVPC ( Figure 2A and B ); the sn-2 moiety was removed preferentially, in keeping with the enzyme’s preference for removing shorter acyl chains from glycerolipids ( Erwin and Munford, 1990 ; Gorelik et al, 2018 ; Munford and Hunter, 1992 ). PGPC or POVPC treated with AOAH (dPGPC or dPOVPC) had greatly reduced ability to induce cell death ( Figure 2C and D ) and IL-1β release ( Figure 2E and F ) in Pam3-primed macrophages, while Pam3 stimulated similar levels of IL-6 production ( Figure 2E ) in the presence of either oxPLs or deacylated oxPLs.…”

Section: Resultsmentioning

confidence: 95%

A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury in mice

Zou

Goodwin²,

Saleem³

et al. 2021

eLife

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Oxidized phospholipids have diverse biological activities, many of which can be pathological, yet how they are inactivated in vivo is not fully understood. Here, we present evidence that a highly conserved host lipase, acyloxyacyl hydrolase (AOAH), can play a significant role in reducing the pro-inflammatory activities of two prominent products of phospholipid oxidation, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine. AOAH removed the sn-2 and sn-1 acyl chains from both lipids and reduced their ability to induce macrophage inflammasome activation and cell death in vitro and acute lung injury in mice. In addition to transforming Gram-negative bacterial lipopolysaccharide from stimulus to inhibitor, its most studied activity, AOAH can inactivate these important danger-associated molecular pattern molecules and reduce tissue inflammation and injury.

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“…To find out if the enzyme can deacylate oxPLs, we incubated PGPC and POVPC with purified recombinant human AOAH (rhAOAH) for 2 or 4 h. Analysis using LC-MS showed that AOAH can remove the sn-2 oxidized fatty acyl chain and sn-1 palmitate from both PGPC and POVPC (Fig. 2A, B); the sn-2 moiety was removed preferentially, in keeping with the enzyme's preference for removing shorter acyl chains from glycerolipids (Erwin and Munford, 1990;Gorelik et al, 2018;Munford and Hunter, 1992). AOAH treatment greatly reduced the ability of PGPC and POVPC to induce cell death (Fig.…”

Section: Aoah Deacylates and Inactivates Oxplsmentioning

confidence: 82%

“…AOAH was originally found to cleave the ester bonds that attach the piggyback (secondary) fatty acyl chains to the primary 3-hydroxy acyl chains in the lipid A moiety of LPS (Hall and Munford, 1983;Munford and Hall, 1986). AOAH-deacylated (tetraacyl) LPS has greatly reduced stimulatory potency and can inhibit LPS signaling by competing with LPS for binding to LPS-binding protein, soluble and membrane CD14, and MD-2 (Erwin and Munford, 1990;Kitchens et al, 1992;Munford and Hall, 1986;Munford and Hall, 1989). Subsequent studies have found that AOAH plays a significant role in inactivating both exogenously-administered LPS and LPS derived from intestinal commensal Gramnegative bacteria (Lu et al, 2013;Lu et al, 2008;Lu et al, 2005;Qian et al, 2018;Shao et al, 2011;Shao et al, 2007;Zou et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury

Zou

Goodwin²,

Saleem³

et al. 2021

Preprint

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Oxidized phospholipids have diverse biological activities, many of which can be pathological, yet how they are inactivated in vivo is not fully understood. Here we present evidence that a previously unsuspected lipase, acyloxyacyl hydrolase (AOAH), can play a significant role in reducing the pro-inflammatory activities of two prominent products of phospholipid oxidation, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC). AOAH removed the sn-2 and sn-1 acyl chains from both lipids and reduced their ability to induce macrophage inflammasome activation and cell death in vitro and acute lung injury in vivo. In addition to transforming Gram-negative bacterial lipopolysaccharide from stimulus to inhibitor, its most studied activity, AOAH can inactivate these important danger-associated molecular pattern (DAMP) molecules and reduce tissue inflammation and cell death.

show abstract

Deacylation of structurally diverse lipopolysaccharides by human acyloxyacyl hydrolase.

Cited by 65 publications

References 47 publications

Endotoxemia: methods of detection and clinical correlates

Endotoxemia: methods of detection and clinical correlates

A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury in mice

A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury

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