Our notes and several illustrations on pro-inflammatory and anti-inflammatory lipid mediators generated from arachidonic acid.
Pro-inflammatory and anti-inflammatory lipid mediators generated from arachidonic acid.
Eicosanoid biosynthesis from arachidonic acid as described by Rogero et al., 2020 (1).
Regero et al., 2020 (1):
Arachidonic acid (ARA), an omega-6 fatty acid, and EPA and DHA, omega-3 fatty acids, affect inflammatory and immune responses. In general, eicosanoids derived from EPA and DHA are less inflammatory than those derived from ARA [32]. For example, eicosanoid receptors typically have a lower affinity for the EPA-derived mediator than for the ARA-derived one [10,33–35]. ARA is generally the main precursor of eicosanoid synthesis because the cell membrane composition of most immune cells contains a greater amount of ARA in comparison with other PUFAs, such as EPA [10]. The mobilization of ARA for eicosanoids formation occurs by the action of the enzyme phospholipase A2 (PLA2), which is activated by physiological or pathological stimuli [36]. The released ARA is then enzymatically oxidized through three enzymes: lipoxygenase (LOX), cytochrome P450 and cyclooxygenase (COX), that lead to leukotrienes (LTs), lipoxins, hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) and prostanoids, which include prostaglandins, prostacyclins and thromboxanes (TXs) (Fig. 1)[37]. The prostaglandin E2 (PGE2) is the most studied COX metabolite in immunological regulation. Its synthesis occurs in several cells, including macrophages, dendritic cells,fibroblasts and endothelial cells. PGE2 is involved in vasodilation, endothelial permeability and increase of pain [38]. PGE2 can exert pro-inflammatory and anti-inflammatory actions, and this heterogeneous effect depends in part, on the regulation of the expression of its specific receptors EP1 – EP4, which belong to the G protein-coupled receptor family (GPCR) [38–40]. The PGE2 has been shown to modulate both innate and adaptive immune cells and plays an important role in the link between the two systems, mediated by antigen-presenting cells (APCs) and T lymphocytes [39,41].It contributes to the tissue influx of neutrophils, macrophages and mast cells, and can affect the differentiation and various functions of these cells, such as phagocytosis and degranulation [39]. PGE2 also acts as a regulator of APCs’ function by, for example, promoting activation, maturation and migration of dendritic cells [41]. In T cells, the PGE2 is important to control their differentiation, disrupting the Th1 response and improving the Th2 response, which leads to a reduction in protection against intracellular pathogens [42]. However, PGE2 can suppress the expression of MHC class II molecules, decrease natural killer (NK) cell activity and reduce the activation of T cells [34,41]
Fig. 1. Eicosanoid biosynthesis from arachidonic acid [ARA]. In response to various stimuli, ARA is released from cell membranes by phospholipase A2 [PLA2]. Free ARA can be metabolized to eicosanoids through the epoxygenase P-450, cyclooxygenase [COX 1 and 2], or lipoxygenases [5-LOX, 12-LOX and 15-LOX] pathways. In epoxygenase P-450, ARA is metabolized to epoxyeicosatrienoic acids [EETs]. The COX enzymes catalyze the conversion of ARA into intermediate prostaglandin G2 [PGG2] and then into prostaglandin H2 [PGH2]. PGH2 acts as a substrate for the generation of biologically active products such as prostaglandins [PGD2, PGE2, PGF2α], thromboxanes [TXA2 and TXB2] and the prostacyclin [PGI2], together these metabolites are called prostanoids. In the presence of aspirin, COX-2 is acetylated [indicated by‘Ac’], which enhances the COX-2-catalyzed formation of 15-R-hydroxyeicosatetraenoic acid [15R -HETE] which can be converted by 5- LOX into the called aspirin-triggered lipoxins [LXA4 and LXB4]. LOX converts ARAfirst to the respective hydroperoxy-eicosatetraenoic acids [5, 12, and 15 – HpETEs] to produce the corresponding hydroxy-eicosatetraenoic acid [5, 12 and 15 – HETEs]. 5-HpETE is also further metabolized to form leukotriene [LT] A4 by 5-LOX. LTA4 is later converted to LTB4, LTC4, LTD4, and LTE4. The 15-HETE lead to the formation of lipoxins by 15-LOX. Based in Dennis & Norris [2015] and Harizi et al., [2008]. Source: Rogero, 2020.
Function of essential polyunsaturated fatty acids in the production of families of bioactive lipid mediators from Serhan and Savill, 2005.
Figure 2 Function of essential polyunsaturated fatty acids in the production of families of bioactive lipid mediators. (a) Arachidonic acid is the precursor of eicosanoids, which have distinct functions as proinflammatory mediators. A series of prostaglandins and leukotrienes has specific actions pivotal to the progression of inflammation 71,72 . Arachidonic acid–derived epoxyeicosatetraenoic acid (EET) generated by cytochrome P450 enzymes may also be important here73,74 . Through cell-cell interactions, exemplified by platelet leukocytes in the vasculature and/or polymorphonuclear cell– mucosa interactions, lipoxins are generated that serve as ‘stop signals’ and promote resolution and serve as endogenous anti-inflammatory mediators self-limiting the course of inflammation. The essential omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid (C20:5 and C22:6) are converted to new families of lipid mediators that are pivotal in promoting resolution (as in b). Resolvins of the E series such as RvE1 are generated from eicosapentaenoic acid, and resolvins of the D series such as RvD1 as well as the protectins such as neuroprotectin D1 (NPD1) are generated from DHA, for which neural systems are enriched 10,11,13,14,75 . (b) Aspirin affects the formation of resolvin E1 by acetylating cyclooxygenase 2 in vascular endothelial cells that, in a ‘stereoselective’ way, can generate 18R-H(p)EPE (hydroperoxyeicosapentaenoic acid) that is picked up through transcellular metabolism by leukocytes and converted by a lipoxygenase-like mechanism to resolvin E1. The complete stereochemistries of resolvin E1 and one of its receptors have been identified 51 . Notably, biosynthesis of resolvin E1 can also be initiated by P450-like enzymes in microbes 10 . Aspirin also affects the formation of D-series resolvins and catalytically switches cyclooxygenase 2 to a 17R-lipoxygenase-like mechanism that serves to generate 17R-series resolvin D 11 . Aspirin also affects the formation of protectins and neuroprotectins by a similar mechanism and generates compounds carrying the 17Repimer at the alcohol at carbon 17 in neuroprotectin D1 and other protectins. LOX, lipoxygenase; H(p)DHA, hydroperoxydocosahexaenoic acid.
Source: Serhan and Savill, 2005.
Selected references:
1. Rogero et al. Free Radical Biology and Medicine 156 (2020) 190–199
![Fig. 1. Eicosanoid biosynthesis from arachidonic acid [ARA]. In response to various stimuli, ARA is released from cell membranes by phospholipase A2 [PLA2]. Free ARA can be metabolized to eicosanoids through the epoxygenase P-450, cyclooxygenase [COX 1 and 2], or lipoxygenases [5-LOX, 12-LOX and 15-LOX] pathways. In epoxygenase P-450, ARA is metabolized to epoxyeicosatrienoic acids [EETs]. The COX enzymes catalyze the conversion of ARA into intermediate prostaglandin G2 [PGG2] and then into prostaglandin H2 [PGH2]. PGH2 acts as a substrate for the generation of biologically active products such as prostaglandins [PGD2, PGE2, PGF2α], thromboxanes [TXA2 and TXB2] and the prostacyclin [PGI2], together these metabolites are called prostanoids. In the presence of aspirin, COX-2 is acetylated [indicated by‘Ac'], which enhances the COX-2-catalyzed formation of 15-R-hydroxyeicosatetraenoic acid [15R -HETE] which can be converted by 5- LOX into the called aspirin-triggered lipoxins [LXA4 and LXB4]. LOX converts ARAfirst to the respective hydroperoxy-eicosatetraenoic acids [5, 12, and 15 - HpETEs] to produce the corresponding hydroxy-eicosatetraenoic acid [5, 12 and 15 - HETEs]. 5-HpETE is also further metabolized to form leukotriene [LT] A4 by 5-LOX. LTA4 is later converted to LTB4, LTC4, LTD4, and LTE4. The 15-HETE lead to the formation of lipoxins by 15-LOX. Based in Dennis & Norris [2015] and Harizi et al., [2008]. Source: Rogero, 2020.](https://medical-en.nneandersphysiologicalliteracy.com/wp-content/uploads/2020/07/image-40.png)
