IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2−/− Mice via Peroxisome Proliferator-Activated Receptor-γ Activation

Coste, Agnès; Lagane, Céline; Filipe, Cédric; Authier, Hélène; Galès, Amandine; Bernad, José; Douin‐Echinard, Victorine; Lepert, Jean-Claude; Balard, Patricia; Linas, M. D.; Arnal, Jean‐François; Auwerx, Johan; Pipy, Bernard

doi:10.4049/jimmunol.180.7.4939

Cited by 32 publications

(37 citation statements)

References 53 publications

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“…Enhancement in host defense by PPAR␥ agonists has also been noted in other infectious agents such as Candida albicans, Klebsiella pneumoniae, and Staphylococcus aureus (25)(26)(27)(28)(51)(52)(53)(54). Overall, these findings point toward a key role of PPAR␥ in the macrophage immune response, where the function of PPAR␥ goes beyond an anti-inflammatory role and extends into modulation of host defense.…”

Section: Discussionmentioning

confidence: 71%

“…By binding to PPAR response elements in target genes, PPARs control the expression of broad networks of genes that regulate diverse and fundamental cellular processes, including metabolism and inflammation (20). In recent years, many studies have described the enhancement of host defenses by PPAR␥ in response to infection by various pathogens (25)(26)(27)(28). We sought to delineate one such mechanism by which PPAR␥ agonists can potentially induce downstream effects, such as the upregulation of PON-2, known for its quorum-quenching properties (15).…”

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confidence: 99%

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Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

et al. 2016

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fThe pathogenic profile of Pseudomonas aeruginosa is related to its ability to secrete a variety of virulence factors. Quorum sensing (QS) is a mechanism wherein small diffusible molecules, specifically acyl-homoserine lactones, are produced by P. aeruginosa to promote virulence. We show here that macrophage clearance of P. aeruginosa (PAO1) is enhanced by activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR␥). Macrophages treated with a PPAR␥ agonist (pioglitazone) showed enhanced phagocytosis and bacterial killing of PAO1. It is known that PAO1 QS molecules are inactivated by PON-2. QS molecules are also known to inhibit activation of PPAR␥ by competitively binding PPAR␥ receptors. In accord with this observation, we found that infection of macrophages with PAO1 inhibited expression of PPAR␥ and PON-2. Mechanistically, we show that PPAR␥ induces macrophage paraoxonase 2 (PON-2), an enzyme that degrades QS molecules produced by P. aeruginosa. Gene silencing studies confirmed that enhanced clearance of PAO1 in macrophages by PPAR␥ is PON-2 dependent. Further, we show that PPAR␥ agonists also enhance clearance of P. aeruginosa from lungs of mice infected with PAO1. Together, these data demonstrate that P. aeruginosa impairs the ability of host cells to mount an immune response by inhibiting PPAR␥ through secretion of QS molecules. These studies define a novel mechanism by which PPAR␥ contributes to the host immunoprotective effects during bacterial infection and suggest a role for PPAR␥ immunotherapy for P. aeruginosa infections.

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

et al. 2016

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“…Consistent with our findings, Katsifa et al (21) showed that human monocytes' phagocytosis is increased through mannose receptors in response to IL-13. Later, a series of studies delineated the mechanisms of IL-13 action in a mouse model: i.e., IL-13 increases Dectin-1 and mannose receptor expression by activating PPAR-g, a critical transcription factor for M2 macrophage differentiation, which, in turn, increases M2 macrophage phagocytic activity (22)(23)(24). It is worth noting that human macrophages tend to differentiate into an M2 type in the presence of C. albicans (25), which suggests that animals possess safeguards at multiple stages of Th2 immunity against Candida infection.…”

Section: Discussionmentioning

confidence: 99%

IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells

Tran

Kim

et al. 2015

The Journal of Immunology

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Susceptibility to systemic Candida albicans infection is determined by immune resistance, as well as by the ability to control Candida-induced immunopathologies. We showed previously that exogenous IL-33 can increase resistance to peritoneal C. albicans infection by regulating multiple steps of the neutrophil anti-Candida response. In this study, using a mouse model of systemic candidiasis, we observed that IL-33 administration limited fungal burden and inflammation and increased survival. In kidneys, IL-33 seemed to directly act on neutrophils and CD4+ T cells: IL-33 administration enhanced fungal clearance by increasing neutrophil phagocytic activity without which Candida proliferation was uncontrollable. In contrast, IL-33 stimulated CD4+ T cells to produce IL-13, which, in turn, drove the polarization of macrophages toward the M2 type. Furthermore, the absence of IL-13 abolished IL-33–mediated polarization of M2 macrophages and renal functional recovery. In addition, IL-33 and IL-13 acted synergistically to increase M2 macrophage polarization and its phagocytic activity. Overall, this study identifies IL-33 as a cytokine that is able to induce resistance and tolerance and suggests that targeting resistance and tolerance simultaneously with therapeutic IL-33 may benefit patients with systemic candidiasis.

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“…Accordingly, macrophages from these infected mice display an intermediate activation phenotype (47) that is predominantly M2. Although evidence indicates that alternatively activated macrophages are more susceptible to some intracellular pathogens, including Cryptococcus neoformans (49), IL-13 was found to attenuate gastrointestinal candidiasis in normal and immunodeficient RAG-2 Ϫ/Ϫ mice, and this protection was correlated with recruitment of macrophages overexpressing the mannose receptor to the intestinal mucosa (12).…”

Section: Discussionmentioning

confidence: 99%

“…Oral colonization and infection of mice with C. albicans trigger macrophage recruitment to the mucosa of the oral cavity (9), stomach (10,71), and cecum (12), suggesting that these cells play a role in resistance to mucosal candidiasis (68). Activated macrophages have the capacity to kill C. albicans by their production of the reactive oxygen intermediates (ROIs) O 2 Ϫ and H 2 O 2 , by the formation of peroxynitrite from O 2 Ϫ and the reactive nitrogen intermediate NO, and by oxygen-independent candidacidal mechanisms (68)(69)(70)(71)73).…”

mentioning

confidence: 99%

Macrophage-Mediated Responses toCandida albicansin Mice Expressing the Human Immunodeficiency Virus Type 1 Transgene

Goupil¹,

Trudelle²,

Dugas³

et al. 2009

Infect Immun

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The critical impairments of innate and adaptive immunity that cause susceptibility to mucosal candidiasis in human immunodeficiency virus (HIV) infection have not been fully determined. We therefore conducted an analysis of macrophage-mediated responses to Candida albicans in transgenic (Tg) mice expressing Nef, Env, and Rev of HIV type 1 (HIV-1) in CD4 ؉ T cells, dendritic cells, and macrophages and developing an AIDS-like disease (CD4C/HIV MutA Tg mice). Macrophages were successfully recruited to the oral and gastric mucosae of these Tg mice in response to chronic carriage of C. albicans and displayed polarization toward an alternatively activated phenotype. Functionally, peritoneal macrophages from uninfected Tg mice exhibited increased phagocytosis of C. albicans and enhanced production of interleukin 6 and monocyte chemoattractant protein 1, demonstrating that the HIV-1 transgene independently activates selected macrophage functions. Production of H 2 O 2 by macrophages from Tg mice primed with gamma interferon and treated with phorbol 12-myristate 13-acetate or C. albicans was moderately reduced, but expression of the HIV-1 transgene did not alter production of nitric oxide or reduce killing of C. albicans. A knockout of the inducible nitric oxide synthase (NOS2) gene in these Tg mice did not augment oral or gastrointestinal burdens during chronic carriage of C. albicans or cause systemic dissemination, likely due to a redundancy provided by partially preserved production of H 2 O 2 and oxygen-independent candidacidal mechanisms. Thus, the macrophage response to C. albicans is largely preserved in these Tg mice, and no functional macrophage defect appears to primarily determine the susceptibility to mucosal candidiasis.

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IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2−/− Mice via Peroxisome Proliferator-Activated Receptor-γ Activation

Cited by 32 publications

References 53 publications

Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells

Macrophage-Mediated Responses toCandida albicansin Mice Expressing the Human Immunodeficiency Virus Type 1 Transgene

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