Abstract
Lipid-derived signaling molecules known as eicosanoids have integral roles in mediating immune and inflammatory processes across metazoans. This includes the function of prostaglandins and their cognate G protein-coupled receptors (GPCRs) to employ their immunological actions. In insects, prostaglandins have been implicated in the regulation of both cellular and humoral immune responses, yet in arthropods of medical importance, studies have been limited. Here, we describe a prostaglandin E2 receptor (AgPGE2R) in the mosquito Anopheles gambiae and demonstrate that its expression is most abundant in oenocytoid immune cell populations. Through the administration of prostaglandin E2 (PGE2) and AgPGE2R-silencing, we demonstrate that prostaglandin E2 signaling regulates a subset of prophenoloxidases (PPOs) and antimicrobial peptides (AMPs) that are strongly expressed in populations of oenocytoids. We demonstrate that PGE2 signaling via the AgPGE2R significantly limits both bacterial replication and Plasmodium oocyst survival. Additional experiments establish that PGE2 treatment increases phenoloxidase (PO) activity through the increased expression of PPO1 and PPO3, genes essential to anti-Plasmodium immune responses that promote oocyst killing. We also provide evidence that the mechanisms of PGE2 signaling are concentration-dependent, where high concentrations of PGE2 promote oenocytoid lysis, negating the protective effects of lower concentrations of PGE2 on anti-Plasmodium immunity. Taken together, our results provide new insights into the role of PGE2 signaling on immune cell function and its contributions to mosquito innate immunity that promote pathogen killing.
Highlights
Eicosanoids are lipid-derived signaling molecules that include prostaglandins (PGs), leukotrienes (LTs), lipoxins (LXAs), and epoxyeicosatrienoic acid (EETs), that serve important roles in immune regulation [1,2,3]
Based on our earlier observations of AgPGE2R localization in oenocytoid cell populations (Figures 1D and S4), we explored what role prostaglandin E2 (PGE2) signaling may have on prophenoloxidase (PPO) expression. qRT-PCR analysis demonstrates that a subset of PPOs which includes PPO1, PPO3, PPO7 and PPO8 were upregulated in response to PGE2 treatment (Figures 2A and S7), which corresponds to those PPOs most enriched in oenocytoid populations [22] (Figure S5)
Prostaglandins have been implicated in insect cellular immune responses such as hemocyte spreading and chemotaxis, nodule formation, melanization, and encapsulation [10, 38, 39], yet have only been examined in limited studies in An. gambiae [11]
Summary
Eicosanoids are lipid-derived signaling molecules that include prostaglandins (PGs), leukotrienes (LTs), lipoxins (LXAs), and epoxyeicosatrienoic acid (EETs), that serve important roles in immune regulation [1,2,3]. Evidence suggests that these responses are evolutionally conserved across Metazoa, where eicosanoids significantly influence insect cellular immunity [4,5,6,7,8,9,10]. Our understanding of eicosanoid-mediated immune regulation in mosquitoes has remained incomplete due to the lack of characterized eicosanoid biosynthesis pathways and cognate receptors that are required to initiate eicosanoid signaling. While previous studies have linked PGE2 signaling to mosquito immunity [4, 11, 13], its cognate prostaglandin receptor has not yet been described in mosquitoes, leaving our understanding of prostaglandin signaling on immune function incomplete
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