IL-1α and IL-1β promote NOD2-induced immune responses by enhancing MAPK signaling

Li, Sushan; Deng, Ping; Wang, Manzhi; Liu, Xueting; Jiang, Manli; Jiang, Bimei; Li, Yang; Hu, Jinyue

doi:10.1038/s41374-019-0252-7

Cited by 37 publications

(26 citation statements)

References 60 publications

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“…Third, our study demonstrated that administration of either TNF-α or IL-1β in mice and cultured primary microglia could upregulate NOD1 and RIP2 expression. Consistent with our findings, previous studies found that treatment of intestinal epithelial cells with TNF-α or treatment of a series of immune cells with IL-1β led to a significant increase in expression of NOD2 (another member of the NLR family) [36,55]. The possible mechanism responsible for NOD1 and RIP2 upregulation by TNF-α/IL-1β may be as follows.…”

Section: Discussionsupporting

confidence: 91%

“…The possible mechanism responsible for NOD1 and RIP2 upregulation by TNF-α/IL-1β may be as follows. First, the interaction between TNF-α and the TNF-α receptor or between IL-1β and the IL-1 receptor can trigger the activation of NF-κB [36,55], which contributes to the upregulation of NOD1 and its adaptor RIP2. Second, endoplasmic reticulum (ER) stress, which can be initiated in response to TNF-α/IL-1β [56,57], was recently reported to contribute to the interaction of tumour necrosis factor (TNF) receptorassociated factor 2 (TRAF2) with NOD1 and lead to NOD1 activation [58,59].…”

Section: Discussionmentioning

confidence: 99%

“…Overall, we speculate that the reduction in NOD1 and RIP2 expression induced by these three inhibitors (SP600125, SB202190, BAY11-7082) and the reductions in JNK/P38 MAPK and NF-κB activation induced by not only their specific inhibitors but also the other two inhibitors likely resulted from the reduced inflammatory cytokines downstream of NOD1/RIP2 signalling, and that crosstalk might occur between NOD1/RIP2 signalling and inflammatory cytokines. To further explore whether NOD1 and RIP2 were indeed upregulated in the presence of the inflammatory cytokines IL-1β and TNF-α, cultured primary microglia stimulated with IL-1β (20 ng/ml) [36] or TNF-α (20 ng/ml) [37] alone or in combination were investigated, and our results showed significant increases in NOD1 and RIP2 protein levels following 24 h of IL-1β or TNF-α stimulation in primary microglia. A marked synergistic impact on NOD1 and RIP2 expression was detected in response to combined administration of IL-1β plus TNF-α, and there were no significant differences between IL-1β and TNF-α stimulation alone (Fig.…”

Section: Nod1/rip2 Inhibition Ameliorated Ich-induced Brain Damage Anmentioning

confidence: 92%

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NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice

Wang

et al. 2020

J Neuroinflammation

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Background Secondary brain damage caused by the innate immune response and subsequent proinflammatory factor production is a major factor contributing to the high mortality of intracerebral haemorrhage (ICH). Nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signalling has been reported to participate in the innate immune response and inflammatory response. Therefore, we investigated the role of NOD1/RIP2 signalling in mice with collagenase-induced ICH and in cultured primary microglia challenged with hemin. Methods Adult male C57BL/6 mice were subjected to collagenase for induction of ICH model in vivo. Cultured primary microglia and BV2 microglial cells (microglial cell line) challenged with hemin aimed to simulate the ICH model in vitro. We first defined the expression of NOD1 and RIP2 in vivo and in vitro using an ICH model by western blotting. The effect of NOD1/RIP2 signalling on ICH-induced brain injury volume, neurological deficits, brain oedema, and microglial activation were assessed following intraventricular injection of either ML130 (a NOD1 inhibitor) or GSK583 (a RIP2 inhibitor). In addition, levels of JNK/P38 MAPK, IκBα, and inflammatory factors, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) expression, were analysed in ICH-challenged brain and hemin-exposed cultured primary microglia by western blotting. Finally, we investigated whether the inflammatory factors could undergo crosstalk with NOD1 and RIP2. Results The levels of NOD1 and its adaptor RIP2 were significantly elevated in the brains of mice in response to ICH and in cultured primary microglia, BV2 cells challenged with hemin. Administration of either a NOD1 or RIP2 inhibitor in mice with ICH prevented microglial activation and neuroinflammation, followed by alleviation of ICH-induced brain damage. Interestingly, the inflammatory factors interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), which were enhanced by NOD1/RIP2 signalling, were found to contribute to the NOD1 and RIP2 upregulation in our study. Conclusion NOD1/RIP2 signalling played an important role in the regulation of the inflammatory response during ICH. In addition, a vicious feedback cycle was observed between NOD1/RIP2 and IL-1β/TNF-α, which could to some extent result in sustained brain damage during ICH. Hence, our study highlights NOD1/RIP2 signalling as a potential therapeutic target to protect the brain against secondary brain damage during ICH.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Nod1/rip2 Inhibition Ameliorated Ich-induced Brain Damage Anmentioning

confidence: 92%

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NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice

Wang

et al. 2020

J Neuroinflammation

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“…MAP kinases (ERK, JNK, p38) play a key role in the modulation of cell growth and differentiation and regulate inflammatory and immune responses. 34,35 According to Park JS, the p38 MAP kinase plays a primary role in inducing pro-inflammatory cytokine expression in LPS-induced neutrophils. 36 In our present study, we found that ERK, JNK and p38 were all activated in HBeAg-induced macrophages.…”

Section: Discussionmentioning

confidence: 99%

Negative feedback loop of ERK/CREB/miR‐212‐3p inhibits HBeAg‐induced macrophage activation

Bian

Xie

Yang

et al. 2020

J Cellular Molecular Medi

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The activation of liver macrophages is closely related to liver injury after HBV infection. Our previous results demonstrated that HBeAg played a key role in inducing macrophage activation. As we all know, miRNAs are involved in the regulation of multiple immune cell functions. Meanwhile, we have shown that miR‐155 positively regulates HBeAg‐induced macrophage activation and accelerates liver injury. Subsequently, based on our previous miRNA sequencing results, we further evaluated the role of miR‐212‐3p called ‘neurimmiR’ in HBeAg‐induced macrophages in this study. First, miR‐212‐3p expression was significantly elevated in HBeAg‐treated macrophages. Meanwhile, we found up‐regulation of miR‐212‐3p significantly decreased the production of cytokines, whereas knockdown of miR‐212‐3p held the opposite effect by gains and losses of function. Mechanically, although MAPK signal pathway, including ERK, JNK and p38, was activated in HBeAg‐induced macrophages, only ERK promoted the expression of miR‐212‐3p via transcription factor CREB, which was able to bind to the promoter of miR‐212‐3p verified by ChIP assay. Moreover, we further indicated that up‐regulated miR‐212‐3p inhibited HBeAg‐induced inflammatory cytokine production through targeting MAPK1. In conclusion, miR‐212‐3p was augmented in HBeAg‐stimulated macrophages via ERK/CREB signal pathway and the elevated miR‐212‐3p suppressed inflammatory cytokine production induced by HBeAg through targeting MAPK1.

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“…That is, the SIRT1/ERK pathway was essential for Que protecting against INH‐induced apoptosis. In addition to apoptosis, immune response is another important feature in INH‐induced hepatotoxicity and SIRT1/ERK is also known as a potential regulator of immune process . Hence, SIRT1/ERK‐mediated immune response may be involved in the protective effect of Que on INH hepatotoxicity, which still needs further exploration.…”

Section: Discussionmentioning

confidence: 99%

Quercetin protected against isoniazide‐induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway

Zhang

Tao

et al. 2019

J Biochem & Molecular Tox

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Isoniazid (INH) is one of the most commonly used antituberculosis drugs, but its clinical applications have been limited by severe hepatic toxicity. Quercetin (Que), a natural flavonoid, has been proved to have many medicinal properties. This study aimed to clarify the possible protective effects of Que against INH‐induced hepatotoxicity using HepG2 cells. Our results indicated that Que significantly increased cell viability, superoxide dismutase, and GSH levels, while decreased alanine aminotransferase/aspartate aminotransferase levels. Besides, Que significantly abrogated INH‐induced cell apoptosis by upregulating the expression levels of Bcl‐2 and decreasing the levels of Bax, cleaved caspase‐3, and cleaved caspase‐9. Furthermore, Que obviously reversed the inhibition of INH on Sirtuin 1 (SIRT1) expression and extracellular signal‐regulated kinase (ERK) phosphorylation. Next, the SIRT1 inhibitor EX527 blocked the enhancement of Que upon ERK phosphorylation. Notably, EX527 partially abolished the beneficial effects of Que. In brief, our results provided the first evidence that Que protected against INH‐induced HepG2 cells by regulating the SIRT1/ERK pathway.

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IL-1α and IL-1β promote NOD2-induced immune responses by enhancing MAPK signaling

Cited by 37 publications

References 60 publications

NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice

NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice

Negative feedback loop of ERK/CREB/miR‐212‐3p inhibits HBeAg‐induced macrophage activation

Quercetin protected against isoniazide‐induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway

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