Cyclooxygenase (COX)-2 modulates Toxoplasma gondii infection, immune response and lipid droplets formation in human trophoblast cells and villous explants

Souza, Guilherme de; Silva, Rafaela José; Milián, Iliana Claudia Balga; Rosini, Alessandra Monteiro; Araújo, Thádia Evelyn de; Teixeira, Samuel Cota; Oliveira, Mário Cézar de; Franco, Priscila Silva; Silva, Cláudio Vieira da; Mineo, José Roberto; Silva, Neide Maria; Ferro, Eloísa Amália Vieira; Barbosa, Bellisa Freitas

doi:10.1038/s41598-021-92120-3

Cited by 28 publications

(34 citation statements)

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“…It has been shown that inhibition of the host COX-2 enzyme resulted in the decrease of parasite burden in the brain and intraperitoneal macrophages of Calomys callosus rodents (8). Similar results were observed in human trophoblasts and villous explants treated with COX-2 inhibitors (9). Host lipoxygenases, appear to be involved in the production of anti-inflammatory responses.…”

Section: Introductionsupporting

confidence: 83%

A potentialToxoplasma gondiilipoxygenase is necessary for virulence and associated with the host immune response

Ramírez-Flores

Perdomo

Wilson

et al. 2022

Preprint

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While the asexual cycle of Toxoplasma gondii can occur in any warm-blooded animal, the sexual cycle is restricted to the feline intestine. We previously determined that because cats lack delta-6-desaturase activity in their intestines, they build up excess linoleic acid, which signals T. gondii to undergo sexual development. We hypothesized that T. gondii oxygenates linoleic acid to signal sexual development, so we examined the T. gondii genome for potential lipoxygenases (TgLOX) enzymes. We identified seven potential TgLOXs that were at least 100-fold more abundant in the cat intestinal versus the tissue culture tachyzoite stage. Parasites deleted in TgLOX1 (TgΔLOX1) had no significant growth differences in tissue culture fibroblast cells. Because the sexual development assay begins with brain cysts, we infected mice with TgΔLOX1 and were surprised to find that TgΔLOX1 had reduced virulence. The TgΔLOX1 parasitemia was reduced by 3 days postinfection and largely cleared by 7 days postinfection. At 3 days postinfection, the cytokines IFNγ, IL-6, MCP-1, and TNF-α were significantly reduced in TgΔLOX1-infected mice, which prompted us to examine TgΔLOX1 in IFNγKO mice. We found that IFNγKO mice infected with TgΔLOX1 succumbed to acute infection with the same kinetics as the parental and complemented strains, suggesting the role of TgLOX1 in mice was IFNγ dependent. In tissue culture fibroblasts, TgLOX1 was localized within the parasite, but in leukocytes from infected mice and activated macrophages, TgLOX1 was localized in vesicular structures in the host cytoplasm. These results suggest that TgLOX1 in these vesicular structures modifies the host immune response.ImportanceLipoxygenases are enzymes that catalyze the dioxygenation of polyunsaturated fatty acids such as linoleic and arachidonic acid. These modifications create signaling molecules that are best characterized for modulating the immune response. Deletion of the first lipoxygenase characterized for Toxoplasma gondii (TgLOX1) generated a less virulent strain and infected mice showed a decreased immune response. This virulence defect was dependent on the mouse cytokine IFNγ. TgLOX1 changes location from inside the parasite in tissue culture conditions to vesicular structures within the host immune cells during mouse infection. These results suggest that TgLOX1 plays a role in the modification of the host immune response in mice.

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Section: Introductionsupporting

confidence: 83%

A potentialToxoplasma gondiilipoxygenase is necessary for virulence and associated with the host immune response

Ramírez-Flores

Perdomo

Wilson

et al. 2022

Preprint

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“…Conversely, in granulosa cells of periovulatory follicles, PGE 2 upregulates PLIN2 [93]. And in human trophoblastic cells, COX2 inhibition reduces LD production induced by the intracellular parasite Toxoplasma gondii [94]. These limited studies suggest that PGs may have cell-type specific roles in regulating LD dynamics and lipid storage.…”

Section: Discussionmentioning

confidence: 99%

Adipose triglyceride lipase promotes prostaglandin-dependent actin remodeling by regulating substrate release from lipid droplets

Giedt

Thomalla

Johnson

et al. 2021

Preprint

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To ensure fertility, it is paramount to understand the factors controlling oocyte quality. One incompletely characterized factor contributing to oocyte quality is lipids. In somatic cells, a key regulator of lipid metabolism is lipid droplets (LDs), the sites of intracellular fat storage. Yet the role of LDs in fertility is poorly understood. Here we use Drosophila oogenesis as a model for uncovering if and how LDs promote egg development. LD accumulation in nurse cells coincides with dynamic actin remodeling necessary for late-stage follicle morphogenesis and fertility. Loss of major LD proteins, including PLIN2, Jabba, and ATGL, disrupts both actin bundle formation and cortical actin integrity; this unusual phenotype is also seen when Pxt, the enzyme responsible for prostaglandin (PG) synthesis, is missing. Further, both pharmacologic and genetic loss of PG synthesis or loss of PLIN2 or Jabba impairs intracellular LD dispersal. These similar phenotypes suggest that PGs and LD proteins act in the same pathway. Dominant genetic interaction studies indicate that there are three actin regulatory pathways: PLIN2 regulates actin remodeling independent of PG signaling, whereas Jabba and ATGL act in two separate PG-dependent pathways to regulate actin remodeling. We find that neither Jabba nor ATGL modulate the levels of Pxt or its localization to the endoplasmic reticulum. As ATGL is a triglyceride lipase, we hypothesize that it may release arachidonic acid (AA), the substrate for PG production, from triglycerides stored in LDs. Indeed, lipidomic analysis reveals the presence of AA-containing triglycerides in ovaries. In addition, exogenous AA is toxic and reduction of ATGL ameliorates toxicity; these observations suggest that ATGL indeed generates free AA. Our studies provide the first evidence that LDs and their associated proteins regulate PG signaling to control actin remodeling. In particular, we propose that ATGL releases AA from LDs to drive PG synthesis necessary for follicle development. We speculate that the same pathways are conserved across organisms to regulate oocyte development and promote fertility.

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“…To the best of our knowledge, here is the first study showing Giardia -induced COX-2/PGE2 enhancement in macrophages. However, some studies have indicated that COX-2/PGE2 can induce anti-inflammatory profiles in cells including macrophages or tissues infected by some intracellular protozoan parasites including Toxoplasma gondii , Trypanosoma cruzi , or Leishmania [ 42 – 46 ]. The difference might be due to different modes of parasitism (extracellular versus intracellular).…”

Section: Discussionmentioning

confidence: 99%

COX-2 is required to mediate crosstalk of ROS-dependent activation of MAPK/NF-κB signaling with pro-inflammatory response and defense-related NO enhancement during challenge of macrophage-like cell line with Giardia duodenalis

et al. 2022

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Giardia duodenalis, the causative agent of giardiasis, is among the most important causes of waterborne diarrheal diseases around the world. Giardia infection may persist over extended periods with intestinal inflammation, although minimal. Cyclooxygenase (COX)-2 is well known as an important inducer of inflammatory response, while the role it played in noninvasive Giardia infection remains elusive. Here we investigated the regulatory function of COX-2 in Giardia-induced pro-inflammatory response and defense-related nitric oxide (NO) generation in macrophage-like cell line, and identified the potential regulators. We initially found that Giardia challenge induced up-regulation of IL-1β, IL-6, TNF-α, prostaglandin (PG) E2, and COX-2 in macrophages, and pretreatment of the cells with COX-2 inhibitor NS398 reduced expressions of those pro-inflammatory factors. It was also observed that COX-2 inhibition could attenuate the up-regulated NO release and inducible NO synthase (iNOS) expression induced by Giardia. We further confirmed that Giardia-induced COX-2 up-regulation was mediated by the phosphorylation of p38 and ERK1/2 MAPKs and NF-κB. In addition, inhibition of reactive oxygen species (ROS) by NAC was shown to repress Giardia-induced activation of MAPK/NF-κB signaling, up-regulation of COX-2 and iNOS, increased levels of PGE2 and NO release, and up-expressions of IL-1β, IL-6, and TNF-α. Collectively, in this study, we revealed a critical role of COX-2 in modulating pro-inflammatory response and defense-related NO production in Giardia-macrophage interactions, and this process was evident to be controlled by ROS-dependent activation of MAPK/NF-κB signaling. The results can deepen our knowledge of anti-Giardia inflammatory response and host defense mechanisms.

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Cyclooxygenase (COX)-2 modulates Toxoplasma gondii infection, immune response and lipid droplets formation in human trophoblast cells and villous explants

Cited by 28 publications

References 100 publications

A potentialToxoplasma gondiilipoxygenase is necessary for virulence and associated with the host immune response

A potentialToxoplasma gondiilipoxygenase is necessary for virulence and associated with the host immune response

Adipose triglyceride lipase promotes prostaglandin-dependent actin remodeling by regulating substrate release from lipid droplets

COX-2 is required to mediate crosstalk of ROS-dependent activation of MAPK/NF-κB signaling with pro-inflammatory response and defense-related NO enhancement during challenge of macrophage-like cell line with Giardia duodenalis

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