Role of <i>miRNA</i>-<i>146a</i> in the regulation of the innate immune response and cancer

Williams, Andrew E.; Perry, Mark M.; Moschos, Sterghios A.; Larner-Svensson, Hanna; Lindsay, Mark A.

doi:10.1042/bst0361211

Cited by 190 publications

(158 citation statements)

References 56 publications

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“…IRAK1, TRAF6, and IRF5 mRNA are regulated by the antiinflammatory miRNA miR-146a (34,35). Therefore, we evaluated the expression of miR-146a in alveolar macrophages after acid aspiration.…”

Section: Akt2-deficient Macrophages Overexpress Mir-146a Which Supprmentioning

confidence: 99%

“…Additionally, TLR4 signaling was shown to play an important role in alveolar macrophage activation in animal models of ALI (12,32,33). TLR4 signaling is regulated by the antiinflammatory miRNA, miR-146a, which targets and suppresses downstream TLR4 mediators, such as TNFR-associated factor (TRAF)-6, IRAK1, and IRF5 (34,35). Yet, the roles of the miR146a macrophage activation phenotype and aseptic inflammation have not been investigated.…”

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confidence: 99%

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Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

146

106

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Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2−/− mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2−/− mice compared with WT mice. Alveolar macrophages from acid-injured Akt2−/− mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2−/− mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2−/− mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2−/− macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

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“…IRAK1, TRAF6, and IRF5 mRNA are regulated by the antiinflammatory miRNA miR-146a (34,35). Therefore, we evaluated the expression of miR-146a in alveolar macrophages after acid aspiration.…”

Section: Akt2-deficient Macrophages Overexpress Mir-146a Which Supprmentioning

confidence: 99%

mentioning

confidence: 99%

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

146

106

View full text Add to dashboard Cite

show abstract

“…Work from us and others has implicated miR-146a as a negative feedback regulator of NF-B activation in innate immune cells (Taganov et al, 2006;Williams et al, 2008;Hou et al, 2009;Boldin et al, 2011;Zhao et al, 2011). This prompted us to investigate the role of miR-146a in regulating NF-B activity in T cells, given that NF-B activation is a critical signaling event induced by TCR stimulation (Schulze-Luehrmann and Ghosh, 2006).…”

Section: Mir-146a Modulates Tcr-induced Activation Of Nf-b In Cd4 + mentioning

confidence: 99%

miR-146acontrols the resolution of T cell responses in mice

Yang¹,

Boldin²,

Yu³

et al. 2012

J Cell Biol

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“…The increased expression of miRNA-146a by cadmium may represent inflammatory response because miRNA-146 expression is known to be regulated by the NF-κB transcription factor, involved in inflammation and innate immunity (Williams et al 2008;Curtale et al 2010). Hossain et al (2012) showed further evidence for cadmium epigenetic effects in peripheral leucocytes from 202 non-smoking women from the northern Argentinean Andes.…”

Section: Epigenetic Effects and Metabolic Adaptationmentioning

confidence: 94%

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

Satarug

2012

Tohoku J. Exp. Med.

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Many decades after an outbreak of severe cadmium poisoning, known as Itai-itai disease, cadmium continues to pose a significant threat to human health worldwide. This review provides an update on the effects of this environmental toxicant cadmium, observed in numerous populations despite modest exposure levels. In addition, it describes the current knowledge on the link between heme catabolism and glycolysis. It examines novel functions of heme oxygenase-2 (HO-2) that protect against type 2-diabetes and obesity, which have emerged from diabetic/obese phenotypes of the HO-2 knockout mouse model. Increased cancer susceptibility in type-2 diabetes has been noted in several large cohorts. This is a cause for concern, given the high prevalence of type-2 diabetes worldwide. A lifetime exposure to cadmium is associated with pre-diabetes, diabetes, and overall cancer mortality with sex-related differences in specific types of cancer. Liver and kidney are target organs for the toxic effects of cadmium. These two organs are central to the maintenance of blood glucose levels. Further, inhibition of gluconeogenesis is a known effect of heme, while cadmium has the propensity to alter heme catabolism. This raises the possibility that cadmium may mimic certain HO-2 deficiency conditions, resulting in diabetic symptoms. Intriguingly, evidence has emerged from a recent study to suggest the potential interaction and co-regulation of HO-2 with the key regulator of glycolysis: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4). HO-2 could thus be critical to a metabolic switch to cancer-prone cells because the enzyme PFKFB and glycolysis are metabolic requirements for cell proliferation and resistance to apoptosis.

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Role of miRNA-146a in the regulation of the innate immune response and cancer

Cited by 190 publications

References 56 publications

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

miR-146acontrols the resolution of T cell responses in mice

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

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