EpOMEs act as immune suppressors in a lepidopteran insect, Spodoptera exigua

Abstract

Epoxyoctadecamonoenoic acids (EpOMEs) are epoxide derivatives of linoleic acid (9,12-octadecadienoic acid) and include 9,10-EpOME and 12,13-EpOME. They are synthesized by cytochrome P450 monooxygenases (CYPs) and degraded by soluble epoxide hydrolase (sEH). Although EpOMEs are well known to play crucial roles in mediating various physiological processes in mammals, their role is not well understood in insects. This study chemically identified their presence in insect tissues: 941.8 pg/g of 9,10-EpOME and 2,198.3 pg/g of 12,13-EpOME in fat body of a lepidopteran insect, Spodoptera exigua. Injection of 9,10-EpOME or 12,13-EpOME into larvae suppressed the cellular immune responses induced by bacterial challenge. EpOME treatment also suppressed the expression of antimicrobial peptide (AMP) genes. Among 139 S. exigua CYPs, an ortholog (SE51385) to human EpOME synthase was predicted and its expression was highly inducible upon bacterial challenge. RNA interference (RNAi) of SE51385 prevented down-regulation of immune responses at a late stage (> 24 h) following bacterial challenge. A soluble epoxide hydrolase (Se-sEH) of S. exigua was predicted and showed specific expression in all development stages and in different larval tissues. Furthermore, its expression levels were highly enhanced by bacterial challenge in different tissues. RNAi reduction of Se-sEH interfered with hemocyte-spreading behavior, nodule formation, and AMP expression. To support the immune association of EpOMEs, urea-based sEH inhibitors were screened to assess their inhibitory activities against cellular and humoral immune responses of S. exigua. 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) was highly potent in suppressing the immune responses. The addition of AUDA to a pathogenic bacterium significantly increased bacterial pathogenicity by suppressing host immune defense. In sum, this study demonstrated that EpOMEs play a crucial role in facilitating anti-inflammatory responses in S. exigua.

Eicosanoid Signaling in Insect Immunology: New Genes and Unresolved Issues

“…Vatanparast et al [ 29 ] also introduced a new class of oxylipins in the biology of their model, S. exigua . These are oxygenated LA derivatives, epoxyoctadecamonoenoic acids (EpOMEs).…”

“…These are oxygenated LA derivatives, epoxyoctadecamonoenoic acids (EpOMEs). For background, Vatanparast et al [ 29 ] provided the chemical structures and outlined EpOME biosynthesis, beginning with release of LA from cellular PLs by a PLA 2 , an oxygenation step by a cytochrome P450 monooxygenase (CYP) and hydroxylation by an epoxide hydrolase. They determined the substantial presence of the compounds, nearly 1000 pg/g 9,10-EpOME and >2000 pg/g 12,13-EpOME in fat body.…”

“…Although PGI 2 acts as a resolving mediator [ 28 ], most eicosanoids activate the immune responses. Furthermore, C18 oxylipins also mediate immune responses in insects, in which EpOMEs negatively mediate the immune responses [ 29 ]. Their metabolized products called dihydroxy-octadecamonoenoates (DiHOMEs) are also detected in mosquito [ 35 ].…”

Parasitic nematode fatty acid- and retinol-binding proteins compromise host immunity by interfering with host lipid signaling pathways

“…We found that Sc-FARs bind to LA and oxidized metabolites of LA in vitro , which may suggest their preferred in vivo binding partners. Our metabolomics studies showed that arachidonic acid, 9(10)- and 12(13)-EpOME, and 13-HODE, which are known to modulate diverse physiological functions in mammals and have been shown to regulate immunity in insects (Vatanparast et al, 2020). 13-HODE has anti-inflammatory functions in mammalian immunity and is often increased under oxidative stress triggered during a disease response, are depleted in the hemolymph of FAR expressing flies (Thompson et al, 2005; Vangaveti et al, 2010).…”

Biosynthesis of New Epoxy Fatty Acids from C18 Polyunsaturated Fatty Acids by Linoleate 9-Lipoxygenase from Sphingopyxis macrogoltabida

“…Cytochrome p450 epoxygenases convert C18 unsaturated fatty acids, such as oleic acid, linoleic acid, and α-linolenic acid, into 9,10-epoxyoctadecanoic acid (Tsikas et al, 2003); 9,10-epoxy-12Z -octadecenoic acid (Spector and Kim, 2015) and 12,13-epoxy-9Z -octadecenoic acid (Vatanparast et al, 2020); 9,10-epoxy-12Z ,15Z -octadecadienoic acid (Wang et al, 2019), 12,13-epoxy-9Z ,15Z -octadecadienoic acid (Walker et al, 2021), and 15,16-epoxy-9Z ,12Z -octadecadienoic acid (Holt et al, 2015), respectively. Cytochrome p450 epoxygenases convert C20 and C22 PUFAs, such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, into C20 and C22 EFAs, such as 5, 6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, 5,6-, 8,9-, 11,12-, 14,15-, and 17,18-epoxyeicosatetraenoic acid, 7,8-, 10,11-, 13,14-, 16,17-, and 19,20epoxydocosapentaenoic acids, respectively (Spector and Kim, 2015).…”