HMGB1–DNA complex-induced autophagy limits AIM2 inflammasome activation through RAGE

Liu, Liying; Yang, Minghua; Kang, Rui; Dai, Yunpeng; Yu, Yan; Gao, Fei; Wang, Hongmei; Sun, Xiaojun; Li, Xiuli; Li, Jianhua; Wang, Haichao; Cao, Lizhi; Tang, Daolin

doi:10.1016/j.bbrc.2014.06.074

Cited by 60 publications

(48 citation statements)

References 47 publications

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“…In addition to NLRs, non-NLR inflammasomes such as absent in melanoma 2 (AIM2) inflammasome have the ability to detect foreign dsDNA. RAGE is required for both HMGB1/DNA complex-induced AIM2 inflammasome activity and autophagy, although upregulated autophagy subsequently limits inflammasome activity (93). The regulatory mechanisms of inflammasome activation are extremely complex (94).…”

Section: Pyroptosismentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

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123

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The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

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Section: Pyroptosismentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

Self Cite

123

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“…2B and D). A growing body of evidence indicates that similar elimination of signaling molecules play key roles in autophagy-regulated immune responses (53)(54)(55)(56)(57). For instance, microglial autophagy plays an important role in the clearance of extracellular Aβ (β-amyloid) fibrils and the regulation of Aβ-induced inflammation, thereby affecting neuronal viability (53).…”

Section: Discussionmentioning

confidence: 99%

An asymmetrically dimethylarginated nuclear 90 kDa protein (p90aDMA) induced by interleukin (IL)-2, IL-4 or IL-6 in the tumor microenvironment is selectively degraded by autophagy

Xia

Zhao

Liu

et al. 2016

International Journal of Oncology

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Abstract. Protein arginine methylation is a common posttranslational modification resulting in the generation of asymmetric dimethylarginine (aDMA) and symmetric dimethylarginine (sDMA). Currently, the regulation of aDMA or sDMA by hypoxia, nutrient stavation or cytokines in the tumor microenvironment remains largely unknown. Here we show that p90aDMA, p70aDMA and p90sDMA, endogenous proteins containing aDMA or sDMA with mass 70 or 90 kDa, were widely and dominantly expressed in breast cancer cell lines. Notably, it was p90aDMA rather than p90sDMA that accumulated in the nucleus upon stimulation of cancer cells with interleukin (IL)-2, IL-4, IL-6 but not IL-8. In addition, the p90aDMA accumulation could be inhibited after treatment with a global methyltrasferase inhibitor, adenosine-2',3'-dialdehyde (AdOx). It seemed that some endogenous proteins in cancer cells were asymmetrically arginine-methylated upon exposure to some cytokines.. Furthermore, endogenous proteins of aDMA, such as p90aDMA and p70aDMA, were degraded in response to hypoxia, nutrient starvation and rapamycin treatment in breast and cervical cancer cells. IL-2/4/6 slightly increased basal autophagy but slightly decreased the rapamycin-induced autophagy in cancer cells, suggesting that IL-2/4/6 and autophagy inducers play distinct roles in the regulation of aDMA of proteins. Conversely, rapamycin accumulated p90sDMA in MDA-MB-231 and MCF-7 cells. Taken together, our results add a new dimension to the complexity of arginine methylated regulation in response to various stimuli and provide the first evidence that aDMA serves as one specific degradation signal of selective autophagy.

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“…In certain cases DNA likely exits the nucleus in complex with DNA repair proteins MRE11 and RAD50 which are hypothesized to provide degradation protection and deliver DNA molecules to STING [44]; lack of MRE11-Rad50 complex strongly reduced DNA damage-induced immune responses. Alternatively, nuclear exit of DNA in complex with chromatin component HMGB1 has been described and linked to immune activation via the inflammasome [45]. Interestingly inhibition of lysosomal enzyme DNase II leads to cytosolic and lysosomal accumulation of damaged host DNA and augments DNA damage induced immune response [46] which means the system is tightly controlled and excess DNA no longer needed for STING/inflammasome activation likely needs to be degraded to not cause too much inflammation.…”

Section: Why and How Is Genotoxic Damage Visible To The Immune System?mentioning

confidence: 98%