Co-Stimulation of PAFR and CD36 Is Required for oxLDL-Induced Human Macrophages Activation

Ríos, Francisco; Koga, Marianna M.; Ferracini, Matheus; Jancar, Sônia

doi:10.1371/journal.pone.0036632

Cited by 45 publications

(39 citation statements)

References 32 publications

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“…In fact, we have previously observed that in macrophages the PAFR activation by oxidized Low Density Lipoprotein (oxLDL) increased LPS-induced IL-10 production and phosphorylation of ERK1/2 and p38 [16,17]. In the present study, however, the blockage of PAFR by antagonist treatment reduced IL-10 production but did not affect MAPK kinases phosphorylation in DCs.…”

Section: Discussioncontrasting

confidence: 77%

“…Molecular mechanisms underlying these effects involve the production of PAFR ligands and STAT3 activation. Moreover, these mechanisms are different from what we previously observed in macrophages, since they are independent on PGE 2 production, PPARγ, or NF-kB activation [7,16,17]. IL-10 is an anti-inflammatory cytokine produced by macrophages, DCs, and lymphocytes, and is able to regulate the activation of innate and adaptive immune responses.…”

Section: Discussioncontrasting

confidence: 74%

“…Further downstream of TLR4 signaling, the mitogen activated protein kinases (MAPKs) and the nuclear factor-κB (NF-κB) pathways are also activated in IL-10 induction. In fact, we have previously shown that PAFR agonists induced IL-8 and IL-10 production through p38 and ERK1/2 activation in human macrophages [16]. To test if these effects also occurred in LPS-stimulated DCs, cells were pre-treated with WEB2086.…”

Section: Pafr Activation Does Not Modulate Tlr4 Downstream Adaptor Momentioning

confidence: 99%

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Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

Koga¹,

Filgueiras²,

Jancar³

2017

J immuno Biol

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The activation of the platelet-activating factor receptor (PAFR) is associated to a suppressor phenotype in macrophages and dendritic cells (DCs). In the present study, we investigated mechanisms underlying the production of the interleukin 10 (IL-10) through PAFR activation in murine DCs. For this purpose, BALB/c mice bone marrowderived DCs were differentiated by GM-CSF treatment and stimulated with LPS in the presence of the PAFR antagonist WEB2086. Signalling pathways downstream to TLR4 activation were investigated. We found that LPS stimulus induced PAFR ligands generation by DCs, but it did not affect the PAFR expression. The LPS-induced IL-10 production was found to be partially dependent of PAFR, since it was reduced in the presence of WEB2086. The IL-10 production through PAFR activation was independent on CREB and PPARγ, as the treatment with selective inhibitors of these pathways did not affect the IL-10 production. TLR4 adaptor molecules (MyD88 and TRIF) expression, MAPK, or NF-κB (p105/50 and p65 subunits) activation pathways were also excluded, since they were not affected by the treatment with WEB2086. The blockage of PAFR by WEB2086 downregulated the STAT3 (Tyr705) phosphorylation induced by LPS. Additionally, DCs treated with STAT3 inhibitor (S3I-201) showed reduced IL-10 production to the same levels observed in DCs treated with WEB2086. The requirement of STAT3 was confirmed in PAFR-KO DCs, since the STAT3 inhibition did not affect IL-10 production by these cells. Our data show an additional molecular mechanism whereby PAFR contributes to IL-10 production in DCs and support the importance of the PAFR activation in DCs phenotype and function.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussioncontrasting

confidence: 74%

Section: Pafr Activation Does Not Modulate Tlr4 Downstream Adaptor Momentioning

confidence: 99%

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Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

Koga¹,

Filgueiras²,

Jancar³

2017

J immuno Biol

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“…15 PAF or oxidized molecules with PAF-like activity generated during stress situations such as hypoxia can engage the PAFR, which activates intracellular signaling pathways that lead to transcription of pro-inflammatory genes. 16 Although PAF is involved in acute renal dysfunction 17 its role in renal fibrosis and in EMT is not completely known. One of the most used experimental model of CKD is the unilateral ureter obstruction (UUO) model.…”

mentioning

confidence: 99%

Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis

Corrêa-Costa

Andrade-Oliveira

Braga

et al. 2014

Laboratory Investigation

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Platelet-activating factor (PAF) is a lipid mediator with important pro-inflammatory effects, being synthesized by several cell types including kidney cells. Although there is evidence of its involvement in acute renal dysfunction, its role in progressive kidney injury is not completely known. In the present study, we investigated the role of PAF receptor (PAFR) in an experimental model of chronic renal disease. Wild-type (WT) and PAFR knockout (KO) mice underwent unilateral ureter obstruction (UUO), and at kill time, urine and kidney tissue was collected. PAFR KO animals compared with WT mice present: (a) less renal dysfunction, evaluated by urine protein/creatinine ratio; (b) less fibrosis evaluated by collagen deposition, type I collagen, Lysyl Oxidase-1 (LOX-1) and transforming growth factor b (TGF-b) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-b/BMP-7 ratio); (c) downregulation of extracellular matrix (ECM) and adhesion molecule-related machinery genes; and (d) lower levels of pro-inflammatory cytokines. These indicate that PAFR engagement by PAF or PAF-like molecules generated during UUO potentiates renal dysfunction and fibrosis and might promote epithelial-to-mesenchymal transition (EMT). Also, early blockade of PAFR after UUO leads to a protective effect, with less fibrosis deposition. In conclusion, PAFR signaling contributes to a pro-inflammatory environment in the model of obstructive nephropathy, favoring the fibrotic process, which lately will generate renal dysfunction and progressive organ failure.

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“…Here, we observe that the PAFR deficiency led to a decrease in Akt phosphorylation in the liver, an effect that is maximized in HFD. In previous publications, we showed that oxidized lipids induce Akt phosphorylation in macrophages in the absence of insulin and in a PAFR-dependent manner (40). PI3K/Akt pathway activation is associated with M2 macrophages polarization (41).…”

Section: Discussionmentioning

confidence: 80%

PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis

et al. 2016

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PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis. Clinical Science, 130(8), pp. 601-612. (doi:10.1042/cs20150538) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/120744/ cells. Blood monocytes of PAFRKO mice also exhibited a pro-inflammatory phenotype (increased frequency of Lys6C+.cells) and PAFR-ligands were detected in the serum of both PAFRKO and WT. Regarding metabolic parameters, compared to WT, PAFRKO mice had: i) higher weight gain andserum glucose concentration levels; ii) decreased insulin-stimulated glucose disappearance; iii) insulin resistance in the liver; iv) increased expression of Ldlr in the liver. In mice fed HFD, some of these changes were potentiated, particularly in the liver. Thus, it seems that endogenous ligands of PAFR are responsible for maintaining the anti-inflammatory profile of blood monocytes and adipose tissue macrophages under physiological conditions. In the absence of PAFR signaling, monocytes and macrophages acquire pro-inflammatory phenotype, resulting in adipose tissue inflammation and metabolic dysfunction. SummaryWe found an essential role of PAFR in adipose tissue macrophages. The PAFRdeficiency leads to infiltration of pro-inflammatory macrophages in the adipose tissue resulting in weight gain, reduced glucose tolerance, hepatic insulin resistance, followed by hepatic steatosis.Short Title: PAFR is associated with anti-inflammatory macrophages and glucose metabolism

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Co-Stimulation of PAFR and CD36 Is Required for oxLDL-Induced Human Macrophages Activation

Cited by 45 publications

References 32 publications

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis

PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis

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