Plasmalogens and Chronic Inflammatory Diseases

Abstract

It is becoming widely acknowledged that lipids play key roles in cellular function, regulating a variety of biological processes. Lately, a subclass of glycerophospholipids, namely plasmalogens, has received increased attention due to their association with several degenerative and metabolic disorders as well as aging. All these pathophysiological conditions involve chronic inflammatory processes, which have been linked with decreased levels of plasmalogens. Currently, there is a lack of full understanding of the molecular mechanisms governing the association of plasmalogens with inflammation. However, it has been shown that in inflammatory processes, plasmalogens could trigger either an anti- or pro-inflammation response. While the anti-inflammatory response seems to be linked to the entire plasmalogen molecule, its pro-inflammatory response seems to be associated with plasmalogen hydrolysis, i.e., the release of arachidonic acid, which, in turn, serves as a precursor to produce pro-inflammatory lipid mediators. Moreover, as plasmalogens comprise a large fraction of the total lipids in humans, changes in their levels have been shown to change membrane properties and, therefore, signaling pathways involved in the inflammatory cascade. Restoring plasmalogen levels by use of plasmalogen replacement therapy has been shown to be a successful anti-inflammatory strategy as well as ameliorating several pathological hallmarks of these diseases. The purpose of this review is to highlight the emerging role of plasmalogens in chronic inflammatory disorders as well as the promising role of plasmalogen replacement therapy in the treatment of these pathologies.

Plasmalogens Eliminate Aging-Associated Synaptic Defects and Microglia-Mediated Neuroinflammation in Mice

“…There has been an increasing interest in plasmalogens research due to the emerging roles they play in health and diseases ( Su et al, 2019 ; Dorninger et al, 2020 ; Bozelli et al, 2021 ). The reduced level of plasmalogens has been commonly observed in the patients suffering from neurodegenerative disorders and appears to meet Bradford Hill criteria for causal association with neurodegeneration to a considerable extent ( Senanayake and Goodenowe 2019 ).…”

Plasmalogenic Lipid Analogs as Platelet-Activating Factor Antagonists: A Potential Novel Class of Anti-inflammatory Compounds

“…Figure 1 summarizes a variety of proposed biological functions for plasmalogens as antioxidants in addition to their modulatory role in membrane structure and dynamics ( Bozelli et al, 2021 ). The high susceptibility of the vinyl-ether bond at sn-1 position to radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS) as well as to the traces of acids supports their important role as a first-line defense system in biology against oxidative damages ( Zhuo et al, 2021 ; Bozelli et al, 2021 ).…”

“…Figure 1 summarizes a variety of proposed biological functions for plasmalogens as antioxidants in addition to their modulatory role in membrane structure and dynamics ( Bozelli et al, 2021 ). The high susceptibility of the vinyl-ether bond at sn-1 position to radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS) as well as to the traces of acids supports their important role as a first-line defense system in biology against oxidative damages ( Zhuo et al, 2021 ; Bozelli et al, 2021 ). Previously, Deng and colleagues have proposed that plasmalogens carrying PUFA chains may promote intracellular cubic membranes (CM) formation ( Deng et al, 2009 ) with the implication in virus-induced host CM formation ( Deng et al, 2010 ; Deng and Angelova, 2021 ).…”

“…The biosynthesis of plasmalogens starts in the subcellular organelle peroxisome and completed in the endoplasmic reticulum (ER) ( Rangholia et al, 2021 ). Plasmalogen deficiency has been reported to be associated with several human diseases as well as aging ( Bozelli et al, 2021 ; Pham et al, 2021 ). Low levels of plasmalogens have been manifested in Zellweger Syndrome (ZS) ( Heymans et al, 1983 , 1984 ), and Rhizomelic Chondrodysplasia Punctata (RCDP) ( Huffnagel et al, 2013 ; Buchert et al, 2014 ), both belong to the peroxisome biogenesis disorders (PBDs) ( Wanders and Waterham, 2006 ).…”

Plasmalogen Replacement Therapy

“…In the blood, plasmalogens are found within erythrocyte membranes and lipoproteins [78]. Changes in blood plasmalogens have attracted some interest as a potential biomarker for the diagnosis and prognosis of some pathological diseases [79][80][81][82][83][84][85].…”