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Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis

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Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis biomolecules Review Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis Robert M. Schilke y, Cassidy M. R. Blackburn y , Temitayo T. Bamgbose and Matthew D. Woolard * Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; [email protected] (R.M.S.); [email protected] (C.M.R.B.); [email protected] (T.T.B.) * Correspondence: [email protected]; Tel.: +1-(318)-675-4160 These authors contributed equally to this work. y Received: 12 September 2020; Accepted: 13 October 2020; Published: 15 October 2020 Abstract: Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are important regulators of immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression, respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis. Keywords: atherosclerosis; phospholipases; macrophages; T cells; lipins 1. Introduction All cellular membranes are composed mostly of phospholipids. Phospholipids are amphiphilic compounds with a hydrophilic, negatively charged phosphate group head and two hydrophobic fatty acid tail residues [1]. The glycerophospholipids, phospholipids with glycerol backbones, are the largest group of phospholipids, which are classified by the modification of the head group [1]. The negatively charged phosphate head forms an ionic bond with an amino alcohol. This bridges the glycerol backbone to the nitrogenous functional group (amino alcohol). The addition of an amino alcohol largely dictates the quaternary structure of the phospholipid [2]. A smaller but also critical family of phospholipids are the sphingolipids, which have sphingosine as a backbone [3]. The amphiphilic make-up of phospholipids allows them to create lipid bilayers, which make cellular membranes and supply structure to cells. Phospholipids also contribute to cellular responses through the binding of receptors, such as lysophosphatidic acid (LPA) binding to the family of LPA receptors, and sphingosine-1-phosphate (S1P) binding to S1P receptors [4]. Components of phospholipids, such as inositol trisphosphate (IP3), diacylglycerol (DAG), and fatty acids, are substrates for the activation of intracellular receptors (e.g., inositol trisphosphate receptors), cofactors for proteins (e.g., protein kinase C), and transcription factors (e.g., peroxisome proliferator-activated receptors (PPARs) [5]. In addition, free fatty acids are also precursors to the prostanoid family of lipid mediators, which can have a broad array of cellular and physiological effects. Phospholipases are a group of enzymes that cleave phospholipids. Each family of phospholipases cleaves a unique site on a phospholipid or unique phospholipid family. Phospholipase A hydrolyzes the fatty acid esters from the sn-1 (PLA1) or sn-2 (PLA2) position of the glycerol backbones, generating free fatty acids [6]. Phospholipase C (PLC) hydrolyzes the glycerol linkage glycerophosphate bond of the polar head, generating DAG and IP3. Phospholipase D (PLD) hydrolyzes the head group of phospholipids, leaving phosphatide and phosphatidic acid (Figure1). Phosphatidic acid phosphatases Biomolecules 2020, 10, 1449; doi:10.3390/biom10101449 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x 2 of 18 Biomolecules 2020, 10, 1449 2 of 18 Phosphatidic acid phosphatases are a family of enzymes that can cleave phosphate heads from LPA, PA, and S1P (Figure 1). Phosphatidic acid phosphatases can be split into two families of enzymes, the areLPPs, a family which of cleave enzymes phosphate that can cleave heads phosphate of lipids on heads the from external LPA, side PA, andof the S1P plasma (Figure 1membrane,). Phosphatidic and acidlipins, phosphatases which cleave can PA be intracellularly. split into two families Phospholipases of enzymes, are the critical LPPs, regulators which cleave of phosphatethe liberation heads of ofbioactive lipids oncompounds the external contained side of within the plasma phospholipids membrane, and and subsequent lipins, which physiological cleave PA activity intracellularly. of those Phospholipasescompounds. are critical regulators of the liberation of bioactive compounds contained within phospholipids and subsequent physiological activity of those compounds. Figure 1. Schematic representation of phospholipase enzymatic sites on phospholipids. “X” represents aFigure functional 1. Schematic group. Redrepresentation “O” represents of phospholipase oxygen; orange enzymatic “P” represents sites on phosphorus; phospholipids. grey “X” “C” represents carbon;a functional white group. “H” represents Red “O” hydrogen;represents “R” oxygen; represents orange fatty “P” acid represents tails. Figure phosphorus; Created withgrey BioRender.com“C” represents .carbon; white “H” represents hydrogen; “R” represents fatty acid tails. Figure Created with BioRender.com. Atherosclerosis is an immuno-metabolic disease that leads to myocardial infarction, stroke, or suddenAtherosclerosis death [7]. Excessis an immuno circulating‐metabolic cholesterol disease in the that form leads of low-densityto myocardial lipoproteins infarction, (LDLs) stroke, can or besudden deposited death into [7]. theExcess arterial circulating intima. cholesterol If these LDLs in the are form not quicklyof low‐density removed, lipoproteins they can be (LDLs) modified can (e.g.,be deposited to oxidized into LDL the arterial (oxLDL)) intima. through If these a variety LDLs of are enzymatic not quickly and nonenzymaticremoved, they modifications can be modified [8]. Oxidative(e.g., to oxidized stress LDL is associated (oxLDL)) with through the increaseda variety of oxidation enzymatic of and LDL nonenzymatic and increased modifications atherosclerosis [8]. progression.Oxidative stress Oxidative is associated stress occurs with whenthe increased there is an oxidation imbalance of in LDL the ratioand ofincreased reactive atherosclerosis oxygen species (ROS)progression. and antioxidants Oxidative [stress9,10]. occurs ROS oxidize when thethere polyunsaturated is an imbalance fatty in the acids ratio and of apolipoproteinreactive oxygen B-100 species on the(ROS) LDL and [11 antioxidants,12]. Once formed, [9,10]. oxLDLROS oxidize leads tothe the polyunsaturated recruitment and fatty activation acids and of inflammatory apolipoprotein cells B‐ into100 theon the arterial LDL intima. [11,12]. Monocytes Once formed,/macrophages oxLDL leads are the to mainthe recruitment cells recruited and into activation the intimal of inflammatory space to clear bothcells LDLinto the and arterial oxidized intima. LDL. MacrophagesMonocytes/macrophages engulf LDL (non-oxidized) are the main cells via the recruited low-density into the lipoprotein intimal receptorspace to (LDLR).clear both This LDL initiates and oxidized a negative LDL. feedback Macrophages inhibitory engulf loop LDL resulting (non‐ inoxidized) the downregulation via the low‐ anddensity degradation lipoprotein of thereceptor LDLR. (LDLR). The negative This initiates feedback a negative loop reduces feedback LDL uptakeinhibitory to limitloop intracellularresulting in cholesterol.the downregulation However, and after degradation oxidation, macrophageof the LDLR. scavenger The negative receptors, feedback such loop as CD36, reduces increase LDL uptake oxLDL engulfment,to limit intracellular leading cholesterol. to intracellular However, cholesterol after accumulation oxidation, macrophage and lipid droplet scavenger formation. receptors, such as CD36,A increase broad range oxLDL of immuneengulfment, cells leading and immunological to intracellular mediators cholesterol contribute accumulation to atherosclerosis. and lipid Macrophagesdroplet formation. have long been recognized as a key component of the immune response that determine atherosclerosisA broad range severity of [immune13]. It is nowcells welland establishedimmunological that neutrophils,mediators contribute dendritic cells,to atherosclerosis. T cells, and B cellsMacrophages have important have long cellular been responses recognized within as a key atherosclerotic component plaque of the immune lesions as response well [14 ].that Furthermore, determine immuneatherosclerosis mediators severity such [13]. as pro-inflammatory It is now well established cytokines that (IL-1 neutrophils,β, TNF-α, anddendritic IL-6), cells, anti-inflammatory T cells, and B cytokinescells have (IL-10), important and lipidcellular mediators responses such within as prostaglandins atherosclerotic and plaque pro-resolvins lesions also as contribute.well [14]. Pro-inflammatoryFurthermore, immune macrophage mediators responses, such as pro Th1‐inflammatory and Th17 T cytokines cell responses, (IL‐1β, andTNF the‐α, and cytokines IL‐6), anti and‐ prostaglandinsinflammatory cytokines those cells (IL produce‐10), and promote lipid mediators atherosclerotic such progressionas prostaglandins (Figure and2)[ 15pro,16‐resolvins]. By contrast, also pro-resolvins,contribute. Pro macrophage‐inflammatory efferocytosis, macrophage anti-phospholipid responses, Th1 B cell and responses, Th17 T and cell T regulatoryresponses, celland
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