Identification of novel neutrophil very long chain plasmalogen molecular species and their myeloperoxidase mediated oxidation products in human sepsis

Abstract

Plasmalogens are a class of phospholipids containing vinyl ether linked aliphatic groups at the sn- 1 position. Plasmalogens are known to contain 16- and 18-carbon aliphatic groups at the sn- 1 position. Here, we reveal that the human neutrophil plasmenylethanolamine pool uniquely includes molecular species with very long carbon chain (VLC) aliphatic groups, including 20-, 22- and 24-carbon vinyl ether linked aliphatic groups at the sn- 1 position. We identified these novel VLC plasmalogen species by electrospray ionization mass spectrometry methods. VLC plasmalogens were only found in the neutrophil plasmenylethanolamine pool. During neutrophil activation, VLC plasmenylethanolamines undergo myeloperoxidase-dependent oxidation to produce VLC 2-chlorofatty aldehyde and its oxidation product, 2-chlorofatty acid (2-ClFA). Furthermore, plasma concentrations of VLC 2-ClFA are elevated in human sepsis. These studies demonstrate for the first time VLC plasmenylethanolamine molecular species, their myeloperoxidase-mediated chlorolipid products and the presence of these chlorolipids in human sepsis.

Plasmalogen Loss in Sepsis and SARS-CoV-2 Infection

“…One mechanism is that loss of plasmalogen is due to oxidative stress during sepsis. We have previously shown plasma 2-chlorofatty acid levels are elevated in human sepsis ( Meyer et al, 2017 ; Amunugama et al, 2021b ). Furthermore, in this rat sepsis model there are increased levels of 2-chlorofatty acid levels ( Pike et al, 2020 ), which is derived from plasmalogens ( Albert et al, 2001 ; Thukkani et al, 2002 ; Amunugama et al, 2021b ).…”

“…We have previously shown plasma 2-chlorofatty acid levels are elevated in human sepsis ( Meyer et al, 2017 ; Amunugama et al, 2021b ). Furthermore, in this rat sepsis model there are increased levels of 2-chlorofatty acid levels ( Pike et al, 2020 ), which is derived from plasmalogens ( Albert et al, 2001 ; Thukkani et al, 2002 ; Amunugama et al, 2021b ). During sepsis the tissue plasmalogen pool or the specific plasmalogen molecular species targeted by HOCl has not been determined.…”

“…Tissue and plasma lipids were extracted in the presence of internal standards (see Supplementary Table S1 ) by a modified Bligh-Dyer extraction as previously described ( Bligh and Dyer, 1959 ; Maner-Smith et al, 2020 ; Pike et al, 2020 ; Amunugama et al, 2021b ). Individual choline and ethanolamine glycerophosphospholipids were detected using selected reaction monitoring (see Supplementary Table S1 for transitions) with an Altis TSQ mass spectrometer equipped with a Vanquish UHPLC System (Thermo Scientific) with isotopomer corrections for each target molecular species compared to the respective internal standard.…”

“…The vinyl ether aliphatic group attached to the glycerol backbone predominantly contains sixteen and eighteen carbon groups. Recently we have also shown neutrophil plasmalogens contain vinyl ether groups that are greater than twenty carbons in length ( Amunugama et al, 2021b ). Plasmalogens have been suggested to have important roles in biological membranes, which are due, in part, to their unique packing in membranes compared to diacyl phospholipids ( Han and Gross, 1990 ; Han and Gross, 1991 ).…”

Regulation of plasmalogen metabolism and traffic in mammals: The fog begins to lift

“…On the other hand, the use of state-of-the-art lipidomic techniques elucidated an increasing number of less abundant plasmalogen species. From that, it became evident that next to the most common alcohols used by the alkylglyceronephosphate synthase (AGPS)/glyceronephosphate O -acyltransferase (GNPAT) complex to form the ether bond, i.e., C16:0, C18:0 and C18:1, also C20:0 is relatively common and many others with chain lengths from 16 to 24 carbon atoms, either saturated or with one or two double bonds, can exist ( Amunugama et al, 2021 ; Azad et al, 2021 ). Furthermore, recent studies have shown that, apart from the predominant head groups ethanolamine and choline, also serine and inositol can serve as head group ( Acar et al, 2007 ), whereas the broad range of fatty acyl residues at sn -2 has long been known.…”