Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages

Yun, Bogeon; Lee, Hee-Jung; Jayaraja, Sabarirajan; Suram, Saritha; Murphy, Robert C.; Leslie, Christina C.

doi:10.1074/jbc.m116.714873

Cited by 21 publications

(27 citation statements)

References 96 publications

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“…The activity of CPLA2α is regulated by intracellular calcium mobilization and phosphorylation by mitogen-activated protein kinases (MAPKs). CPLA2α triggers PGE 2 biosynthesis through COX-1 and can induce expression of Il10, Ptgs2 , and Nr4a2 , while suppressing Tnf α expression in MAPK by increasing cAMP (Yun et al, 2016). Other results suggest that in the Golgi apparatus, cPLA2, COX-2 and mPGES-1 can provide a beneficial system for PGE 2 formation (Evans and Leslie, 2004; Yuan and Smith, 2015).…”

Section: Group Iva Cytosolic Phospholipase A2 (Cpla2α)mentioning

confidence: 99%

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Liu

Wang

et al. 2016

Front. Microbiol.

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Candida is an important opportunistic fungal pathogen, especially in biofilm associated infections. The formation of a Candida biofilm can decrease Candida sensitivity to antifungal drugs and cause drug resistance. Although many effective antifungal drugs are available, their applications are limited due to their high toxicity and cost. Seeking new antifungal agents that are effective against biofilm-associated infection is an urgent need. Many research efforts are underway, and some progress has been made in this field. It has been shown that the arachidonic acid cascade plays an important role in fungal morphogenesis and pathogenicity. Notably, prostaglandin E2 (PGE2) can promote the formation of a Candida biofilm. Recently, the inhibition of PGE2 has received much attention. Studies have shown that cyclooxygenase (COX) inhibitors, such as aspirin, ibuprofen, and indomethacin, combined with fluconazole can significantly reduce Candida adhesion and biofilm development and increase fluconazole susceptibility; the MIC of fluconazole can be decrease from 64 to 2 μg/ml when used in combination with ibuprofen. In addition, in vivo studies have also confirmed the antifungal activities of these inhibitors. In this article, we mainly review the relationship between PGE2 and Candida biofilm, summarize the antifungal activities of COX inhibitors and analyze the possible antifungal activity of microsomal prostaglandin E synthase-1 (MPGES-1) inhibitors; additionally, other factors that influence PGE2 production are also discussed. Hopefully this review can disclose potential antifungal targets based on the arachidonic acid cascade and provide a prevailing strategy to alleviate Candida albicans biofilm formation.

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Section: Group Iva Cytosolic Phospholipase A2 (Cpla2α)mentioning

confidence: 99%

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Liu

Wang

et al. 2016

Front. Microbiol.

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“…Ptgs2 is the key enzyme in prostaglandin biosynthesis, and acts both as a dioxygenase and as a peroxidase. It has been found that in C. albicans -infected resident peritoneal macrophages, activation of group IV RprcA cytosolic phospholipase A2 (cPLA2α) by calcium- and mitogen-activated protein kinases triggers the rapid production of prostaglandins I2 and E2 through cyclooxygenase (COX)-1 (74). The Chemokine (CC-motif) ligand 3 (CCL3), which was upregulated 4.6-fold, has been shown to play important roles in the acute inflammatory response to C. albicans corneal infection (75) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Setting off the Alarms:Candida albicansElicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches

Singh

Song

et al. 2019

Preprint

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24Candida albicans has been associated with a number of human diseases that pertain to 25 the gastrointestinal (GI) tract. However, the details of how gut-associated lymphoid tissues 26 (GALT) such as Peyer's patches (PPs) in the small intestine play a role in immune surveillance 27 and microbial differentiation, and what mechanisms PP use to protect the mucosal barrier in 28 response to fungal organisms such as C. albicans, are still unclear. We particularly focus on PPs 29 as they are the immune sensors and inductive sites of the gut that influence inflammation and 30 tolerance. We have previously demonstrated that CD11c + phagocytes located in the sub-31 epithelial dome (SED) within PPs sample C. albicans. To gain insight on how specific cells 32within PPs sense and respond to the sampling of fungi, we gavaged mice with C. albicans strains 33 ATCC 18804 and SC5314 as well as Saccharomyces cerevisiae. We measured the differential 34 gene expression of sorted CD45 + B220 + B-cells, CD3 + T-cells, and CD11c + DCs within the first 35 24 hrs post-gavage using nanostring nCounter® technology. The results reveal that at 24 hrs, PP 36 phagocytes were the cell type that displayed differential gene expression. These phagocytes were 37 both able to sample C. albicans and able to discriminate between strains. In particular, strain 38 ATCC 18804 upregulated fungal specific pro-inflammatory genes in CD11c + phagocytes 39 pertaining to innate and adaptive immune responses. Interestingly, PP CD11c + phagocytes 40 differentially expressed genes in response to C. albicans that were important in the protection of 41 the mucosal barrier. These results highlight that the mucosal barrier not only responds to C. 42 albicans, but also aids in the protection of the host. 43 Importance 44The specific gene expression changes within PPs that send the warning signals when 45 encountering fungi, and how PPs can discriminate between innocuous S. cerevisiae or different 46 strains of C. albicans during early stages of sampling, have not been elucidated. Here we show 47 that within the first 24 hours of sampling, CD11c + phagocytes were not only important in 48 sampling, but they were the cell type that exhibited clear differential gene expression. These 49 differentially expressed genes play important dual roles in inflammation, chemotaxis, and fungal 50 specific recognition, as well as maintaining homeostasis and protection of the mucosal barrier. 51Using nanostring technology, we were also able to demonstrate that PPs can distinguish between 52 different strains of C. albicans and can "set off the alarms" when necessary. 53 54

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“…PGE 2 has wide-ranging effects on phagocytes, most of which converge on immunosuppression [49]. For instance, PGE 2 reduces the phagocytosis of fungi by macrophages [32, 50, 51] and polarizes both fungi-exposed macrophages and DCs towards an immunoregulatory phenotype, characterized by a decreased secretion of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and an increased expression of suppressive factors such as interleukin (IL)-10 and arginase-1 [21–27]. Hence, PGE 2 secreted by C. albicans proximal to or engulfed by intestinal phagocytes might dampen their uptake of more fungi, phagosome maturation, and/or production of inflammatory, antifungal factors.…”

Section: Discussionmentioning

confidence: 99%

Fungal symbionts produce prostaglandin E₂to promote their intestinal colonization

Tan

Lim

Tan

et al. 2018

Preprint

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1314 Candida albicans is a ubiquitous fungal symbiont that resides on diverse human barrier surfaces. Both 15 mammalian and fungal cells can convert arachidonic acid into the lipid mediator, prostaglandin E2 16 (PGE 2 ), but the physiological significance of fungal-derived PGE 2 remains elusive. Here we report 17 that a C. albicans mutant deficient in PGE 2 production suffered a loss of competitive fitness in the 18 murine gastrointestinal (GI) tract and that PGE 2 supplementation mitigated this fitness defect.19 Impaired fungal PGE 2 production affected neither the in vitro fitness of C. albicans nor hyphal 20 morphogenesis and virulence in either systemic or mucosal infection models. Fungus-derived PGE 2 21 improved intra-GI fitness of C. albicans by diminishing the killing of C. albicans by phagocytes.22 Consequently, ablation of colonic phagocytes abrogated the fitness boost conferred by fungal PGE 2 .23 These observations suggest that C. albicans has evolved the capacity to produce PGE 2 from 24 arachidonic acid, a host-derived precursor, to promote its own colonization of the host gut. Analogous 25 mechanisms might undergird host-microbe interactions of other symbiont fungi. 263 27 Author Summary 28 29 Candida albicans is a symbiont fungus that resides in the gut of a majority of people without 30 provoking disease. However, resident C. albicans can bloom and turn pathogenic in a subset of 31 individuals who are immunocompromised due to infections or chemotherapy or who suffer a disruption 32 of their intestinal microbial community due to antibiotic use. However, the fungal and host factors that 33 regulate the fitness of C. albicans as a symbiont or an invasive pathogen remain poorly understood.34 Here we focused on the physiological role of fungus-derived prostaglandin E2 (PGE 2 ) in the fitness of 35 C. albicans using a PGE 2 -deficient C. albicans strain and mouse models of infections and intestinal 36 symbiosis. We found that fungal PGE 2 , contrary to previously described functions of promoting 37 virulence, played no role in fungal pathogenicity in vivo. Instead, fungal PGE 2 specifically augmented 38 the ability of C. albicans to colonize the gut, in part by reducing fungal killing by intestinal phagocytes.39 Our results suggest that fungal PGE 2 synthetic pathways may be prophylactically targeted in 40 individuals susceptible to invasive infections.41 4 42 Introduction 43 44 Candida albicans is one of the most successful fungal symbionts in humans, colonizing 40-45 80% of individuals in industrialized nations and typically representing the predominant species within 46 the fungal microbiota [1, 2]. In healthy people, C. albicans dwells on diverse barrier sites of the body, 47 including the oral cavity, skin, female reproductive tract, and the intestines, where it does not cause 48 symptomatic disease [1, 2]. However, C. albicans can turn pathogenic and result in mucosal or life-49 threatening invasive bloodstream infections under a variety of conditions that compromise host 50 immunity, damage barr...

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Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages

Cited by 21 publications

References 96 publications

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Setting off the Alarms:Candida albicansElicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches

Fungal symbionts produce prostaglandin E₂to promote their intestinal colonization

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Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages

Cited by 21 publications

References 96 publications

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Setting off the Alarms:Candida albicansElicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches

Fungal symbionts produce prostaglandin E2to promote their intestinal colonization

Contact Info

Product

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Fungal symbionts produce prostaglandin E₂to promote their intestinal colonization