Biosynthesis of specialized proresolving mediators (SPMs)

A host’s normal protective response to tissue injury or pathogenic infection is acute inflammation. The condition of acute inflammation is created by the release of pro-inflammatory lipid mediators such as leukotrienes (LTs) and prostaglandins (PGs) that launch a series of signaling cascades to destroy invading pathogens and to repair damaged tissue (Libby 2007). The potent chemotactic agent leukotriene B4 (LTB4) promotes the recruitment of neutrophils (PMNs) to inflamed tissues, while the prostaglandins E2 and D2 (PGE2 and PGD2) further accelerate the inflammatory process. If left unchecked, the inflammatory response can initiate chronic systemic inflammatory disorders associated with cardiovascular disease, rheumatoid arthritis, periodontal disease, asthma, diabetes, inflammatory bowel disease (IBD), Alzheimer’s disease and age-related macular degeneration (AMD). The specific role by which inflammation contributes to their pathogenesis is not fully understood.<br><br>To prevent the onset of chronic inflammation, a <i>lipid mediator class switch</i> is thought to occur from the initial actions of pro-inflammatory lipid mediators to the anti-inflammatory and pro-resolving actions of lipoxins, resolvins, protectins and maresins (collectively called specialized proresolving mediators (SPMs)). Nanopicogram quantities of different lipid mediators are generated at different times during the evolution of the inflammatory response and these mediators coincide with distinct cellular events. The class switch activates leukocyte translational regulation of the enzymes required to produce pro-resolving lipid mediators (Levy et al. 2001). Each family of these PSMs exert specialized actions, including blocking neutrophil recruitment, promoting the recruitment and activation of monocytes, as well as mediating the nonphlogistic phagocytosis and lymphatic clearance of apoptotic neutrophils by activated macrophages (ie without inducing inflammation) and mediating tissue regeneration. Eventually, through the combined actions of these mediators, the resolution of inflammation is completed and homeostasis is reached (Serhan 2010, Bannenberg & Serhan 2010, Freire & Van Dyke 2013, Serhan et al. 2014).<br><br>SPMs are derived from polyunsaturated fatty acids (PUFAs) (Molfino et al. 2017). PUFAs of the ω-3 series are essential nutrients since they cannot be produced by humans (Duvall & Levy 2016) and are primarily found in dietary fish oils (Calder 2013) and in plants (Baker et al. 2016). The ω-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPAn-3) circulate in the bloodstream after dietary intake and are easily incorporated into cellular membranes in a time- and dose-dependent manner (Calder 2009), as well as being present in inflammatory exudates (Kasuga et al. 2008). They can be mobilised by phospholipase A2 from cellular membranes on injury or infection when they are converted to exudate SPMs (Serhan et al. 2002) to interact with local immune cells (Kasuga et al. 2008). EPA is the source for E-series resolvins while DHA is the source for D-series resolvins, protectins, maresins and sulfido conjugates in tissue regeneration mediators (Serhan et al. 2017). The ω-6 fatty acid arachidonic acid (AA) is the source for lipoxins. ω-3 or ω-6 PUFA docosapentaenoic acids (DPAn-3 and DPAn-6) are the sources of DPA-derived resolvins, protectins and maresins (Vik et al. 2017). Aspirin can also trigger the production of epimeric SPMs via acetylated PTGS2 (prostaglandin G/H synthase, COX2) (Serhan & Chiang 2002). Combinations of oxidation, reduction and hydrolysis can generate numerous SPMs. Electrophilic oxo-derivatives of ω-3 PUFAs are a class of oxidised derivatives that are generated in macrophages and neutrophils by the actions of 5-lipoxygenase, cyclooxygenase-2 and acetylated cyclooxygenase-2, followed by dehydrogenation. Being electrophilic, oxo-derivative SPMs reversibly bind to nucleophilic residues on target proteins, triggering the activation of cytoprotective pathways (Cipollina 2015). The pathways in this section describe the biosynthesis of these SPMs.

宿主对组织损伤或病原体感染的正常保护性反应为急性炎症。急性炎症状态由前列腺素类促炎脂质介质，如白三烯（LTs）和前列腺素（PGs）的释放所引起，这些介质启动一系列信号级联反应，以摧毁入侵病原体并修复受损组织（Libby 2007）。强效的趋化因子白三烯B4（LTB4）促进中性粒细胞（PMNs）向炎症组织募集，而前列腺素E2和D2（PGE2和PGD2）进一步加速炎症过程。如果炎症反应未得到控制，可能会引发与心血管疾病、类风湿性关节炎、牙周病、哮喘、糖尿病、炎症性肠病（IBD）、阿尔茨海默病和年龄相关性黄斑变性（AMD）相关的慢性系统性炎症性疾病。炎症在病理发生机制中的具体作用尚未完全明了。<br><br>为了预防慢性炎症的发生，人们认为发生了一种所谓的“脂质介质类别转换”，即从促炎脂质介质的初始作用到脂氧素、溶酶体素、保护素和马罗辛（统称为专用促解决介质（SPMs））的抗炎和促解决作用的转变。在炎症反应发展的不同阶段，不同种类的脂质介质以纳皮克克量的形式生成，这些介质与不同的细胞事件相对应。类别转换激活了产生促解决脂质介质所需的酶的白细胞翻译调控（Levy et al. 2001）。这些PSMs的每一类都发挥特定的作用，包括阻断中性粒细胞募集，促进单核细胞的募集和活化，以及通过活化的巨噬细胞介导的非炎症性吞噬和淋巴清除凋亡中性粒细胞（即不诱导炎症）以及介导组织再生。最终，通过这些介质的联合作用，炎症得到解决，达到稳态（Serhan 2010，Bannenberg & Serhan 2010，Freire & Van Dyke 2013，Serhan et al. 2014）。<br><br>SPMs源自多不饱和脂肪酸（PUFAs）（Molfino et al. 2017）。ω-3系列的PUFAs是必需的营养素，因为人体无法合成它们（Duvall & Levy 2016），它们主要存在于膳食鱼油（Calder 2013）和植物中（Baker et al. 2016）。ω-3 PUFAs二十碳五烯酸（EPA）、二十二碳六烯酸（DHA）和二十二碳五烯酸（DPAn-3）在膳食摄入后进入血液循环，并以时间和剂量依赖性方式轻松地整合到细胞膜中（Calder 2009），同时也存在于炎症渗出物中（Kasuga et al. 2008）。在损伤或感染时，它们可以从细胞膜中被磷脂酶A2动员出来，转化为渗出物SPMs（Serhan et al. 2002），与局部免疫细胞相互作用（Kasuga et al. 2008）。EPA是E系列溶酶体素的来源，而DHA是D系列溶酶体素、保护素、马罗辛和组织再生介质中硫化物共轭物的来源（Serhan et al. 2017）。ω-6脂肪酸花生四烯酸（AA）是脂氧素的来源。ω-3或ω-6 PUFAs二十二碳五烯酸（DPAn-3和DPAn-6）是DPA衍生溶酶体素、保护素和马罗辛的来源（Vik et al. 2017）。阿司匹林还可以通过乙酰化的PTGS2（前列腺素G/H合酶，COX2）触发异构体SPMs的产生（Serhan & Chiang 2002）。氧化、还原和水解的组合可以生成多种SPMs。ω-3 PUFAs的亲电氧化衍生物是一类氧化衍生物，它们由巨噬细胞和中性粒细胞通过5-脂氧合酶、环氧合酶-2和乙酰化的环氧合酶-2的作用产生，随后进行脱氢。由于是亲电的，氧化衍生物SPMs可逆地结合到靶蛋白上的亲核残基，触发细胞保护途径的激活（Cipollina 2015）。本节描述了这些SPMs的生物合成途径。