PPARγ‐dependent regulation of human macrophages in phagocytosis of apoptotic cells

Májai, Gyöngyike; Sarang, Zsolt; Csomós, Krisztián; Zahuczky, Gábor; Fésüs, László

doi:10.1002/eji.200636398

Cited by 134 publications

(157 citation statements)

References 64 publications

(71 reference statements)

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“…Increased efferocytosis in a time-dependent fashion was also shown in zymosan-induced peritonitis animal models, which was mirrored by peroxisome proliferatoractivated receptor (PPAR)-c expression and activation [34]. PPAR-c and Rac1 are positive regulators of efferocytosis of apoptotic cells [6,[35][36][37]. Exposure to apoptotic cells has been shown to induce cyclo-oxygenase (COX)-2-derived production of prostaglandins (PGs), including PGE 2 and PGJ 2 , which are endogenous stimulants for Rac1 and PPAR-c activation, respectively [38,39].…”

Section: Discussionmentioning

confidence: 99%

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Lee

Moon²,

Lee³

et al. 2012

Eur Respir J

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Apoptotic cell clearance by macrophages and neighbouring tissue cells induces hepatocyte growth factor (HGF) secretion. HGF plays a key role in alveolar epithelial regeneration and reconstruction after lung injury. Direct in vivo exposure to apoptotic cells enhances HGF production, resulting in attenuation of pulmonary injury.We investigated the direct effect of in vivo exposure to apoptotic cells in bleomycin-stimulated lungs (2 days old) on HGF induction. Furthermore, sequential changes of bleomycin-induced HGF production following apoptotic cell instillation related to the changes in inflammatory and fibrotic responses were assessed.At 2 h after apoptotic cell instillation into bleomycin-stimulated lungs, the levels of HGF mRNA and protein production, and apoptotic cell clearance by alveolar macrophages were enhanced. Furthermore, HGF induction persistently increased following apoptotic cell instillation up to 21 days after bleomycin treatment. Apoptotic cell instillation attenuated bleomycin-induced proinflammatory mediator production, inflammatory cell recruitment and total protein levels. Apoptotic cell instillation also induced antiapoptotic and antifibrotic effects. These antiinflammatory and antiapoptotic effects could be reversed by co-administration of HGFneutralising antibody.These findings indicate that in vivo exposure to apoptotic cells enhances transcriptional HGF production in bleomycin-stimulated lungs, resulting in attenuation of lung injury and fibrosis.

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Section: Discussionmentioning

confidence: 99%

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Lee

Moon²,

Lee³

et al. 2012

Eur Respir J

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“…Both assays demonstrated major effects of OA-NO 2 on these parameters, together with much smaller effects of fluticasone. Phagocytosis is triggered by interaction with the scavenger receptor CD36, the expression of which is upregulated by PPARg activation (30). OA-NO 2 treatment significantly upregulated CD36 expression by AMs in vitro (Fig.…”

Section: Oa-no 2 Upregulates Pparg and Inhibits Nf-kb Activity In Vitromentioning

confidence: 92%

The Nitrated Fatty Acid 10-Nitro-Oleate Attenuates Allergic Airway Disease

Reddy

Lakshmi

Dornadula

et al. 2013

The Journal of Immunology

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Asthma is a serious, growing problem worldwide. Inhaled steroids, the current standard therapy, are not always effective in this chronic inflammatory disease and can cause adverse effects. We tested the hypothesis that nitrated fatty acids (NFAs) may provide an effective alternative treatment. NFAs are endogenously produced by nonenzymatic reaction of NO with unsaturated fatty acids and exert anti-inflammatory actions both by activating the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)γ and via PPAR-independent mechanisms, but whether they might ameliorate allergic airway disease was previously untested. We found that pulmonary delivery of the NFA 10-nitro-oleic acid (OA-NO2) reduced the severity of murine allergic airway disease, as assessed by various pathological and molecular markers. Fluticasone, an inhaled steroid commonly used to treat asthma, produced similar effects on most end points, but only OA-NO2 induced robust apoptosis of neutrophils and their phagocytosis by alveolar macrophages. This suggests that OA-NO2 may be particularly effective in neutrophil-rich, steroid-resistant severe asthma. In primary human bronchial epithelial cells, OA-NO2 blocked phosphorylation and degradation of IκB and enhanced inhibitory binding of PPARγ to NF-κB. Our results indicate that the NFA OA-NO2 is efficacious in preclinical models of allergic airway disease and may have potential for treating asthma patients.

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“…Macrophage-specific deletion of PPAR-c in mice decreases the efferocytosis of apoptotic cells, while PPARc activation enhances efferocytosis by MDMs [12] and alveolar macrophages from healthy donors [35].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, rosiglitazone inhibits the development of lipopolysaccharide (LPS)-induced airway neutrophilia [10], and pioglitazone inhibits allergic pulmonary inflammation in mice to a similar degree to corticosteroids [11]. In addition to its role in the inflammatory response, PPAR-c is also involved in the regulation of macrophage efferocytosis; PPAR-c deletion reduces macrophage clearance of apoptotic cells [12]. This function of macrophages is important for the resolution of tissue injury.…”

Section: Introductionmentioning

confidence: 99%

The effect of peroxisome proliferator-activated receptor-γ ligands onin vitroandin vivomodels of COPD

et al. 2013

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Peroxisome proliferator-activated receptor (PPAR)-c is expressed in alveolar macrophages. The anti-inflammatory potential of the PPAR-c ligands rosiglitazone and pioglitazone were investigated using in vitro alveolar macrophage models and in vivo animal models relevant to chronic obstructive pulmonary disease (COPD).PPAR-c protein and gene expression in COPD alveolar macrophages was compared with control smokers and never-smokers. COPD macrophages were used to investigate the effects of PPAR-c ligands and corticosteroids on lipopolysaccharide-induced cytokine production, alternative macrophage activation (M2) gene expression and efferocytosis. The effects of PPAR-c ligands in a subchronic tobacco smoke model in mice were investigated.PPAR-c protein expression was similar in COPD patients compared to controls, although increased gene expression levels were observed in COPD patients and control smokers compared to never-smokers. PPAR-c ligands reduced tumour necrosis factor-a and CC chemokine ligand-5, but not CXC chemokine ligand-8, in COPD alveolar macrophages; these effects were generally less than those of the corticosteroid dexamethasone. Rosiglitazone increased M2 gene expression and enhanced efferocytosis of apoptotic neutrophils. Rosiglitazone and pioglitazone attenuated airway neutrophilia in a corticosteroid-resistant mouse model of pulmonary inflammation.We show biological actions of PPAR-c agonists on corticosteroid-resistant disease, tobacco smokeinduced pulmonary inflammation, skewing of macrophage phenotype and clearance of apoptotic neutrophils.@ERSpublications Biological actions of a PPAR-c agonist shown in COPD-relevant models may affect progression and side-effects in patients

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PPARγ‐dependent regulation of human macrophages in phagocytosis of apoptotic cells

Cited by 134 publications

References 64 publications

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

The Nitrated Fatty Acid 10-Nitro-Oleate Attenuates Allergic Airway Disease

The effect of peroxisome proliferator-activated receptor-γ ligands onin vitroandin vivomodels of COPD

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