A20 deficiency causes spontaneous neuroinflammation in mice

Guedes, Renata Padilha; Csizmadia, Eva; Moll, Herwig P.; Ma, Averil; Ferran, Christiane; Silva, Cleide Gonçalves da

doi:10.1186/1742-2094-11-122

Cited by 51 publications

(39 citation statements)

References 88 publications

(97 reference statements)

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“…A20 mRNA was also detected in the cortex and hippocampus of WT mice (26,27). In experimental autoimmune encephalomyelitis models and LPS-induced inflammatory models, A20 is expressed in microglia and astrocytes and suppresses inflammation (28,29). However, our results indicated that after ICH, A20 is mainly expressed in microglia and neurons and seldom in astrocytes, consistent with the cell types that were induced to express A20 after LV-A20 injection.…”

Section: /2supporting

confidence: 34%

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

Meng

Zhao

Zhou

et al. 2017

The Journal of Immunology

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Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20−/− and A20-overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20−/− and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20−/− parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20−/− parabionts compared with A20−/− mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20−/− mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IκBα degradation and NF-κB activation were observed in A20−/− mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH.

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Section: /2supporting

confidence: 34%

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

Meng

Zhao

Zhou

et al. 2017

The Journal of Immunology

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“…To test this hypothesis, we targeted A20 (tumor necrosis factor alpha-induced protein 3 [TNFAIP3]), an anti-inflammatory molecule and primary negative regulator of NF-κB activity (Ma and Malynn, 2012). A20-deficient mice spontaneously develop neuroinflammation, which has been attributed to A20 deficiency in microglia (Guedes et al, 2014). Consistent with this, primary microglia isolated from A20-haplodeficient ( Tnfaip3 +/ − ) mice had an exaggerated TNF and IL-6 secretory response to LPS and saturated fatty acid (palmitate) treatments (Figure S5A).…”

Section: Resultsmentioning

confidence: 99%

Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility

et al. 2017

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SUMMARY Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.

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“…NF-κB and IκB are activated and shifted into the karyon from the cytoplasm. It has been observed that NF-κB was activated in rats with DAI at the early stages of injury (21). Activated NF-κB was identified in the cytoplasm and cell nucleus of neurons after 24 h of injury.…”

Section: Discussionmentioning

confidence: 93%

Neuroprotective effect of berberine against learning and memory deficits in diffuse axonal injury

Wang

Chen

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to assess the neuroprotective effect of berberine against learning and memory deficits in diffuse axonal injury (DAI). DAI rats were orally gavaged with berberine at a dose of 200 mg/kg of body weight for 4 weeks. Behavioral tests were used to analyze the neuroprotective effect of berberine against DAI-induced learning and memory deficits. In the present study, treatment with berberine significantly protected against DAI-induced inhibition of learning and memory in rats. Notably, berberine significantly suppressed the levels of tumor necrosis factor, interleukin-1β and monocyte chemoattractant protein-1, as well as reduced the protein expression levels of nuclear factor-κB, Bcl-2-associated X protein and cytochrome c in DAI rats. In addition, berberine significantly suppressed the protein expression of p38 mitogen-activated protein kinase, activating transcription factor 2 and vascular endothelial growth factor in DAI rats. These results suggested that berberine exhibited a neuroprotective effect against learning and memory deficits in severe DAI through the suppression of inflammation, angiogenesis and apoptosis in a rat model.

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A20 deficiency causes spontaneous neuroinflammation in mice

Cited by 51 publications

References 88 publications

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility

Neuroprotective effect of berberine against learning and memory deficits in diffuse axonal injury

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