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Toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1-dependent IL-1? secretion enhances parasite replication.

ABSTRACT: Alternatively activated macrophages (AAM) are a key feature Th2 immunity and have been associated with a variety of roles during helminth infection. The role this cell subset plays in protozoan infection remain relatively unexplored, herein we describe the effects of a redox enzyme (rTgPrx) derived from Toxoplasma gondii on murine macrophage phenotype in vitro. RTgPrx has been previously associated with the maintainance of parasite oxidative balance. Here our experiments show that rTgPrx promotes AAM as indicated by high arginase-1 (arg-1), YM1 and FIZZ expression via both signal transducer and activator of transcription (STAT)6-dependent and -independent mechanisms. Additionally rTgPrx treatment reduced caspase-1 activity and IL-1? secretion, while simultaneously increasing IL-10 release. Furthermore the in vitro replication of T. gondii (RH strain) was enhanced when macrophages were treated with rTgPrx. This is in contrast with the previously described effects of a Plasmodium berghei ANKA 2-cys-peroxiredoxin that promotes pro-inflammatory cytokine production. These results highlight the role of T. gondii derived redox enzymes as important immune modulators and potentially indicate a role for AAM in modulating immunopathology and promoting parasite replication during T. gondii infection.

SUBMITTER: Marshall ES

PROVIDER: S-EPMC3141401 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1-dependent IL-1β secretion enhances parasite replication.

Marshall Edward S ES Elshekiha Hany M HM Hakimi Mohamed-Ali MA Flynn Robin J RJ

Veterinary research 20110627

Alternatively activated macrophages (AAM) are a key feature Th2 immunity and have been associated with a variety of roles during helminth infection. The role this cell subset plays in protozoan infection remain relatively unexplored, herein we describe the effects of a redox enzyme (rTgPrx) derived from Toxoplasma gondii on murine macrophage phenotype in vitro. RTgPrx has been previously associated with the maintainance of parasite oxidative balance. Here our experiments show that rTgPrx promote ...[more]

PMID: 21707997

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Project description:BACKGROUND:Toxoplasma gondii can invade and replicate in all nucleated cells in a wide range of host species, and infection induces IL-1β production. IL-1β plays central roles in the stimulation of the innate immune system and inflammation. However, little is known of the innate immune responses in human fetal small intestinal epithelial cells (FHs 74 Int cells) after T. gondii infection. METHODS:FHs 74 Int cells were infected with the T. gondii GFP-RH strain. Then, IL-1β production and its mechanisms of action were evaluated using ELISA, MTT cell viability assays, Western blotting, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and gene-specific small interfering RNA (siRNA) transfection. RESULTS:Infection of FHs 74 Int cells by T. gondii triggered significant time- and dose-dependent IL-1β production. Although T. gondii activated NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes in FHs 74 Int cells, NLRP3 levels were consistently and significantly time-dependently increased, while the other inflammasomes were not. Transfection with siRNA targeting NLRP3, cleaved caspase-1 (Casp-1) or ASC significantly reduced T. gondii-induced IL-1β production, whereas T. gondii proliferation was markedly increased. Toxoplasma gondii infection activated P2X7 receptor (P2X7R) levels in FHs 74 Int cells in a time-dependent manner; however, transfection with siRNA targeting P2X7R significantly reduced T. gondii-induced IL-1β secretion and substantially increased T. gondii proliferation, which is mediated by decreased protein expression levels of NLRP3, cleaved Casp-1 and ASC. Collectively, NLRP3-dependent IL-1β secretion is mediated by P2X7R in small intestinal epithelial cells in response to T. gondii infection, thereby controlling parasite proliferation. CONCLUSIONS:This study revealed that the P2X7R/NLRP3 pathway plays important roles in IL-1β secretion and inhibition of T. gondii proliferation in small intestinal epithelial cells. These results not only contribute to our understanding of the mucosal immune mechanisms of T. gondii infection but also offer new insight into the identification of innate resistance in the gut epithelium.

Project description:UnlabelledInterleukin-1? (IL-1?) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1?; however, the host and parasite factors that mediate IL-1? production during T. gondii infection are poorly understood. We report that T. gondii induces IL-1? transcript, processing/cleavage, and release from infected primary human monocytes and THP-1 cells. Treating monocytes with the caspase-1 inhibitor Ac-YVAD-CMK reduced IL-1? release, suggesting a role for the inflammasome in T. gondii-induced IL-1? production. This was confirmed by performing short hairpin RNA (shRNA) knockdown of caspase-1 and of the inflammasome adaptor protein ASC. IL-1? induction required active parasite invasion of monocytes, since heat-killed or mycalolide B-treated parasites did not induce IL-1?. Among the type I, II, and III strains of T. gondii, the type II strain induced substantially more IL-1? mRNA and protein release than did the type I and III strains. Since IL-1? transcript is known to be induced downstream of NF-?B signaling, we investigated a role for the GRA15 protein, which induces sustained NF-?B signaling in a parasite strain-specific manner. By infecting human monocytes with a GRA15-knockout type II strain and a type I strain stably expressing type II GRA15, we determined that GRA15 is responsible for IL-1? induction during T. gondii infection of human monocytes. This research defines a pathway driving human innate immunity by describing a role for the classical inflammasome components caspase-1 and ASC and the parasite GRA15 protein in T. gondii-induced IL-1? production.ImportanceMonocytes are immune cells that protect against infection by increasing inflammation and antimicrobial activities in the body. Upon infection with the parasitic pathogen Toxoplasma gondii, human monocytes release interleukin-1? (IL-1?), a "master regulator" of inflammation, which amplifies immune responses. Although inflammatory responses are critical for host defense against infection, excessive inflammation can result in tissue damage and pathology. This delicate balance underscores the importance of understanding the mechanisms that regulate IL-1? during infection. We have investigated the molecular pathway by which T. gondii induces the synthesis and release of IL-1? in human monocytes. We found that specific proteins in the parasite and the host cell coordinate to induce IL-1? production. This research is significant because it contributes to a greater understanding of human innate immunity to infection and IL-1? regulation, thereby enhancing our potential to modulate inflammation in the body.

Dataset Information

Toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1-dependent IL-1? secretion enhances parasite replication.

Publications

Toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1-dependent IL-1β secretion enhances parasite replication.

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