Comparative distribution of protein components of the A20 ubiquitin-editing complex in normal human brain

Pranski, Elaine L.; Sanford, Carson D. Van; Dalal, Nirjari V.; Orr, Adam L.; Karmali, Dipan; Cooper, Deborah S.; Costa, Nichole; Heilman, Craig J.; Gearing, Marla; Lah, James J.; Levey, Aĺlan I.; Betarbet, Ranjita

doi:10.1016/j.neulet.2012.05.043

Cited by 20 publications

(27 citation statements)

References 30 publications

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“…However, IL-6 and TNF-a levels increased in the A20 2/2 sham group (Fig. 5D), suggesting that A20 deficiency caused spontaneous inflammation in the mouse brain, consistent with previous research (27). In the current study, because of the serious infection and high mortality, we did not perform A20 2/2 -A20 2/2 parabiosis.…”

Section: /2supporting

confidence: 88%

“…The results of the current study indicated that A20 is primarily expressed in neurons in the normal human brain and that more A20 was expressed in the pons, striatum, hippocampus, and medulla compared with the frontal cortex. 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).…”

Section: /2mentioning

confidence: 93%

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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: 88%

Section: /2mentioning

confidence: 93%

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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“…We demonstrated basal A20 mRNA expression in the mouse CX and HC, the two brain structures that were the focus of this study, though the comparative distribution of A20 in the different brain regions varies between mice and humans [14]. We verified that basal A20 mRNA levels in CX and HC decreased by half and were totally absent in brains of A20 HT and KO, respectively.…”

Section: Discussionmentioning

confidence: 55%

A20 deficiency causes spontaneous neuroinflammation in mice

Guedes

Csizmadia

Moll

et al. 2014

J Neuroinflammation

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BackgroundA20 (TNFAIP3) is a pleiotropic NFκB-dependent gene that terminates NFκB activation in response to inflammatory stimuli. The potent anti-inflammatory properties of A20 are well characterized in several organs. However, little is known about its role in the brain. In this study, we investigated the brain phenotype of A20 heterozygous (HT) and knockout (KO) mice.MethodsThe inflammatory status of A20 wild type (WT), HT and KO brain was determined by immunostaining, quantitative PCR, and Western blot analysis. Cytokines secretion was evaluated by ELISA. Quantitative results were statistically analyzed by ANOVA followed by a post-hoc test.ResultsTotal loss of A20 caused remarkable reactive microgliosis and astrogliosis, as determined by F4/80 and GFAP immunostaining. Glial activation correlated with significantly higher mRNA and protein levels of the pro-inflammatory molecules TNF, IL-6, and MCP-1 in cerebral cortex and hippocampus of A20 KO, as compared to WT. Basal and TNF/LPS-induced cytokine production was significantly higher in A20 deficient mouse primary astrocytes and in a mouse microglia cell line. Brain endothelium of A20 KO mice demonstrated baseline activation as shown by increased vascular immunostaining for ICAM-1 and VCAM-1, and mRNA levels of E-selectin. In addition, total loss of A20 increased basal brain oxidative/nitrosative stress, as indicated by higher iNOS and NADPH oxidase subunit gp91phox levels, correlating with increased protein nitration, gauged by nitrotyrosine immunostaining. Notably, we also observed lower neurofilaments immunostaining in A20 KO brains, suggesting higher susceptibility to axonal injury. Importantly, A20 HT brains showed an intermediate phenotype, exhibiting considerable, albeit not statistically significant, increase in markers of basal inflammation when compared to WT.ConclusionsThis is the first characterization of spontaneous neuroinflammation caused by total or partial loss of A20, suggesting its key role in maintenance of nervous tissue homeostasis, particularly control of inflammation. Remarkably, mere partial loss of A20 was sufficient to cause chronic, spontaneous low-grade cerebral inflammation, which could sensitize these animals to neurodegenerative diseases. These findings carry strong clinical relevance in that they question implication of identified A20 SNPs that lower A20 expression/function (phenocopying A20 HT mice) in the pathophysiology of neuroinflammatory diseases.

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“…TRAF6 was also found to be expressed in astrocytes and neurons in the brain [4,39]. Consistently, pJNK and CCL2 are also primarily induced in spinal astrocytes after SNL [12].…”

Section: Discussionmentioning

confidence: 91%

TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling

Jiang

Cao

et al. 2014

Pain

122

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The proinflammatory cytokines TNF-α and IL-1β have been strongly implicated in the pathogenesis of neuropathic pain, but the intracellular signaling of these cytokines in glial cells are not fully understood. Tumor necrosis factor receptor associated factor 6 (TRAF6) plays a key role in signal transduction in the TNF receptor superfamily and the interleukin-1 receptor superfamily. In this study, we investigated the role of TRAF6 in neuropathic pain in mice following spinal nerve ligation (SNL). SNL induced persistent TRAF6 upregulation in the spinal cord. Interestingly, TRAF6 was mainly colocalized with the astrocytic marker GFAP on SNL day 10 and partially expressed in microglia on SNL day 3. In cultured astrocytes, TRAF6 was up-regulated after exposure to TNF-α or IL-1β. TNF-α or IL-1β also increased CCL2 expression, which was suppressed by both siRNA and shRNA targeting TRAF6. TRAF6 siRNA treatment also inhibited the phosphorylation of c-Jun N-terminal kinase (JNK) in astrocytes induced by TNF-α or IL-1β. JNK inhibitor D-NKI-1 dose-dependently decreased IL-1β-induced CCL2 expression. Moreover, spinal injection of TRAF6 siRNA decreased intrathecal TNF-α-or IL-1β-induced allodynia and hyperalgesia. Spinal TRAF6 inhibition via TRAF6 siRNA, shRNA lentivirus, or antisense oligodeoxynucleotides partially reversed SNL-induced neuropathic pain and spinal CCL2 expression. Finally, intrathecal injection of TNF-α-activated astrocytes induced mechanical allodynia, which was attenuated by pretreatment of astrocytes with TRAF6 siRNA. Taken together, the results suggest that TRAF6, upregulated in spinal cord astrocytes in the late phase after nerve injury, maintains neuropathic pain by integrating TNF-α and IL-1β signaling and activating the JNK/CCL2 pathway in astrocytes.

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Comparative distribution of protein components of the A20 ubiquitin-editing complex in normal human brain

Cited by 20 publications

References 30 publications

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

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

A20 deficiency causes spontaneous neuroinflammation in mice

TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling

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