PPARγ Controls Dectin-1 Expression Required for Host Antifungal Defense against Candida albicans

Galès, Amandine; Conduché, Annabelle; Bernad, José; Lefèvre, Lise; Olagnier, David; Béraud, Maryse; Martin‐Blondel, Guillaume; Linas, M. D.; Auwerx, Johan; Coste, Agnès; Pipy, Bernard

doi:10.1371/journal.ppat.1000714

Cited by 83 publications

(77 citation statements)

References 35 publications

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“…Whereas the role of PPARg in modulation of IL-10 expression has been well studied (27,46), the role of TR4 was unclear. CD206 and CD36 are described as the hallmark markers for M2 macrophages (47). The ability of TR4 to modulate the expression of CD206, a M2 macrophage marker, was earlier unknown.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival

Mahajan

Dkhar

Chandra

et al. 2012

The Journal of Immunology

171

195

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Mycobacterium tuberculosis–macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis–macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival

Mahajan

Dkhar

Chandra

et al. 2012

The Journal of Immunology

171

195

View full text Add to dashboard Cite

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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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“…Mice that are biased toward Th2 responsiveness are more susceptible to disseminated (56) and mucosal infection (57) with Candida albicans. However, promotion of M2a polarization in gastrointestinal Candida albicans infection has been shown to limit fungal colonization (58). Finally, in lung infection with Aspergillus fumigatus, generation of Th1/regulatory T cell responses over Th2 responses favor resistance to infection (59), suggesting that M2a polarization would complicate clearance of this organism.…”

Section: Discussionmentioning

confidence: 99%

IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

Nelson

Christmann²,

Metz

et al. 2011

B14. Novel Treatments for Lung Infections: Modulating Immune Responses

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We have recently reported that mice deficient in the myeloid Src-family tyrosine kinases Hck, Fgr, and Lyn (Src triple knockout [TKO]) had augmented innate lung clearance of Pneumocystis murina that correlated with a higher ability of alveolar macrophages (AMs) from these mice to kill P. murina. In this article, we show that despite possessing enhanced killing, AMs from naive Src TKO mice did not demonstrate enhanced inflammatory responses to P. murina. We subsequently discovered that both AMs and lungs from P. murina-infected Src TKO mice expressed significantly greater levels of the M2a markers RELM-α and Arg1, and the M2a-associated chemokines CCL17 and CCL22 than did wild-type mice. IL-4 and IL-13, the primary cytokines that promote M2a polarization, were not differentially produced in the lungs between wild-type and Src TKO mice. P. murina infection in Src TKO mice resulted in enhanced lung production of the novel IL-1 family cytokine IL-33. Immunohistochemical analysis of IL-33 in lung tissue revealed localization predominantly in the nucleus of alveolar epithelial cells. We further demonstrate that experimental polarization of naive AMs to M2a resulted in more efficient killing of P. murina compared with untreated AMs, which was further enhanced by the addition of IL-33. Administration of IL-33 to C57BL/6 mice increased lung RELM-α and CCL17 levels, and enhanced clearance of P. murina, despite having no effect on the cellular composition of the lungs. Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis. Pneumonia caused by NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptwere diagnosed in the year 2009, and 25,000 deaths (19,000 in 2002) were recorded as a result of HIV infection (2). Although the advent of highly active antiretroviral therapy (HAART) has decreased the overall incidence of Pneumocystis carinii pneumonia (3), the mortality rate of those requiring hospitalization remains high (3). A recent retrospective study in an academic medical center found that overall hospital mortality rate to P. jiroveci pneumonia was 11.6%, and in those patients requiring intensive care, 29.0% (4). An additional study summarized the experience with HIV-associated P. carinii pneumonia over a 21-y period in a single center and found that mortality was 10.1% for the period from 1985 through 1989, 16.9% for the period from 1990 through June 1996, and 9.7% for the period from July 1996 through 2006 (i.e., the HAART era) (5). A major concern voiced by this study is the similar mortality associated with P. jiroveci pneumonia pre-and post-HAART.It is widely reported that phagocytosis by alveolar macrophages (AMs) is the predominant mechanism of Pneumocystis murina clearance from the lungs (6-8); however, the mechanisms by which macrophages kill P. murina are not completely understood. It is hypothesized that on phagocytosis, the oxidative burst b...

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PPARγ Controls Dectin-1 Expression Required for Host Antifungal Defense against Candida albicans

Cited by 83 publications

References 35 publications

Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival

Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival

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

IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

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