Associate editor: D. ZeldinProstaglandin E2 as a Regulator of Immunity to Pathogens☆
Introduction
While it is common to think of proteins such as cytokines, growth factors and chemokines as being the principle soluble mediators of host defense against pathogens, a variety of unique lipids can also play important roles in regulating innate and adaptive immune function. Lipid signaling molecules derived from arachidonic acid can have both pro-inflammatory and resolving functions (e.g. through the production of leukotrienes, prostaglandins and resolvins) whereas lipids derived from eicosapentaenoic acid are generally considered inhibitory (Dennis and Norris, 2015, Serhan et al., 2014, Wiktorowska-Owczarek et al., 2015). In this review, we will focus on the synthesis, signaling and impact of one lipid mediator derived from arachidonic acid metabolism known as prostaglandin E2 (PGE2).
Section snippets
PGE2 synthesis
PGE2 belongs to the family of eicosanoids which are lipid hormone-like signaling molecules that have important roles in inflammatory and physiological functions (Dennis & Norris, 2015). Homeostatic levels of eicosanoids are always present in mammalian tissue and dysregulation of these levels can have different physiological outcomes (Dennis and Norris, 2015, Wang and Dubois, 2010). All eicosanoid molecules are produced from the enzymatic modification of arachidonic acid (AA), a polyunsaturated
PGE2 signaling
PGE2 effector functions have been shown to modulate many biological processes including cell proliferation, apoptosis, angiogenesis, inflammation, and immune surveillance. This is due to the ability of PGE2 to signal in both autocrine and paracrine manners through four different types of EP GPCRs, namely EP1, EP2, EP3, and EP4 (Dennis and Norris, 2015, O'Callaghan and Houston, 2015, Regan, 2003, Rogers et al., 2014, Sugimoto and Narumiya, 2007). EP receptors differ in their intracellular
Innate Immune Effectors
The first line of innate immune cells that come in contact with potential pathogens are macrophages and neutrophils. Macrophages can differentiate from monocytes in circulation upon extravasation to tissues, but it is now appreciated that most tissue resident macrophages derive from embryonically-seeded tissue-resident stem cells (Ginhoux and Jung, 2014, Gordon et al., 2014). These macrophages can be influenced by signals in the environment to polarize into various effector cells with functions
PGE2 and inflammasome-dependent IL-1β secretion
One of the most critical cytokines needed to initiate inflammation and innate immune responses is interleukin 1 (IL-1)β which is proteolytically cleaved and activated from an immature precursor protein by caspase-1 as part of a multi-protein complex known as an inflammasome. Inflammasomes react to pathogenic stimuli leading to the activation and secretion of both IL-1β and IL-18. If not properly regulated, overzealous inflammasome activation can lead to a form of caspase-1-dependent cell death
PGE2 and Neutrophil Extracellular Traps (NETs) formation
Neutrophils are the most abundant leukocyte circulating in the blood and are the first recruited cells to the site of infection after tissue sentinel cells encounter pathogens (Lehrer et al., 1988, Nauseef and Borregaard, 2014, Wang, 2004). Upon pathogen recognition, neutrophils can kill microbes by phagocytosis, degranulation (secretion of antimicrobial molecules), and the release of NETs (Papayannopoulos, 2009). NETs are web-like structures of decondensed chromatin containing the
PGE2 and autophagy
Macroauthophagy (herein known as autophagy) is an intracellular homeostatic process for energy conservation in which the cell engulfs cytoplasmic proteins and organelles for degradation (Deretic, Saitoh, & Akira, 2013). It is characterized by formation of a double membrane vesicle termed an “autophagosome” which fuses with the lysosome to create the “autolysosome”, where engulfed material will be destroyed by lysosomal hydrolases (Deretic et al., 2013, Shibutani et al., 2015). Interestingly,
PGE2 and TLR Crosstalk
The recognition of microbial infection is often initiated via interaction of PAMPs with TLRs (Kawai & Akira, 2011). The TLRs are type I membrane-spanning proteins found either on the cell surface or in endosomes that have leucine-rich ectodomains that interact with the PAMPs. Once activated by ligand, the cytosolic toll-IL-1 receptor or TIR domains activate downstream signaling pathways to initiate responses to infection. Each TLR recognizes distinct PAMPs derived from viruses, bacteria, fungi
PGE2 influences on adaptive immunity
Clearance of intracellular pathogens generally involves recognition of the pathogen by an antigen presenting cell (most commonly a dendritic cell, but macrophages and B cells are also known to do this), processing of pathogen proteins and presentation of pathogen peptides on cell surface major histocompatibility complex (MHC) class I and class II proteins where they can interact with CD4 and CD8 T cells capable of recognizing these pathogen peptide-MHC complexes. Instructive cytokine signals
PGE2 and bacterial infection
The role of PGE2 in host defense against bacterial infections has been well described elsewhere (Agard et al., 2013). Thus, we will restrict our focus here on how PGE2 regulates infection by some of the organisms on the World Health Organization's (WHO, 2017; http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf) list of the most critical bacterial pathogens impacting human health which includes Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus
PGE2 and viral infection
Similar to the effects during bacterial infection, PGE2 is also known to impact host defense against viruses (Sander et al., 2017). As described above, modulations of TLR signaling would be expected to impact recognition of viral pathogens. Furthermore, impairments in autophagy could alter viral antigen processing and presentation needed to stimulate adaptive immunity (Deretic et al., 2013). The section above described the ability of PGE2 to limit phagocytosis and generation of reactive oxygen
PGE2 and fungal infection
Prostaglandins have also been studied in fungal infections. As opposed to viral and bacterial pathogens, many yeasts can themselves produce prostaglandins, including PGE2 (Ells et al., 2012, Erb-Downward and Huffnagle, 2007, Erb-Downward and Noverr, 2007, Noverr et al., 2002). Production of PGE2 by yeast has been shown to enhance bacterial growth in mixed biofilms; suggesting that such polymicrobial infections are more difficult to clear (Krause et al., 2015). In addition, Candida albicans is
Conclusions
In this review, we have tried to highlight the varied and complex roles of the lipid mediator, PGE2, in regulating multiple aspects of innate and adaptive immunity. The various actions of PGE2 are summarized in Fig. 3. PGE2 biology is complicated by the fact that many cell types can produce this lipid mediator and many cell types can respond to stimulation of 4 unique EP receptors. PGE2 plays important homeostatic functions, but when induced in response to pathogen stimulation, PGE2 has the
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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Support: This work was supported by NIH grants: AI117229, HL127805 and HL119682 (BBM). GM-C was supported by T32AI007413, a University of Michigan Rackham Merit fellowship and a scholarship from the Miller Fund for Innovative Immunology Research.