Sphk1 mediates neuroinflammation and neuronal injury via TRAF2/NF-κB pathways in activated microglia in cerebral ischemia reperfusion

Su, Dan; Cheng, Yuefeng; Li, Shi; Dai, Dawei; Zhang, Wei; Lv, Mei

doi:10.1016/j.jneuroim.2017.01.015

Cited by 49 publications

(43 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These previous studies revealed the important but distinct role of different TRAF molecules in regulating the pathology of ischemic stroke. In contrast to other TRAFs, TRAF6 uses a distinct interaction motif and acts as a convergence point for the TNFR and TLR families (Song et al, 1997;Muzio et al, 1998;Ye et al, 2002). Here, we demonstrated that TRAF6 promotes cerebral I/R injury by potentiating NF-B-mediated inflammation, Nox2-mediated oxidative stress, and incidental neuronal damage by interacting directly with Rac1.…”

Section: Discussionmentioning

confidence: 74%

“…After cerebral I/R, TRAF1 promotes neuroapoptosis by activating the JNK prodeath pathway and inhibiting Akt cell survival signaling . TRAF2 can activate the JNK1/2, p38 MAPK , or NF-B pathways (Su et al, 2017) to induce apoptosis and inflammation in I/R injured brain. TRAF3 binds to TAK1 and potentiates TAK1-dependent activation of the NF-B, Rac-1, and JNK signaling pathways to regulate inflammation, oxidative stress, and neuronal survival (Gong et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family members (TRAF1-7 in mammals), which are characterized by an N-terminal RING finger motif (except TRAF1) and a C-terminal TRAF domain (except TRAF7), are important adaptor proteins in the assembly of receptor-associated signaling networks that link upstream receptors to downstream effector molecules. Recently, we and others have revealed the functions of TRAF1/2/3/5 in ischemic stroke Lu et al, 2013;Geng et al, 2015;Su et al, 2017). In contrast to other TRAFs, TRAF6 uses a distinct interaction motif presented in its upstream activators (Ye et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1

Li¹,

Qin

Yang

et al. 2017

J. Neurosci.

View full text Add to dashboard Cite

Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury. Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting the TRAF6-Rac1 axis may provide a novel therapeutic strategy for stroke recovery.

show abstract

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1

Li¹,

Qin

Yang

et al. 2017

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…TNF and IL-6 were found to be the predominant cytokine signature of the primary microglia of SGPL1 fl/fl/Nes mice. In a rat model of cerebral ischemia reperfusion, S1P addition to primary microglia was found to elevate the levels of the cytokine IL-17A (Lv, Zhang, Dai, Zhang, & Zhang, 2016), which was found to be mediated by the sphingosine kinase1-TRAF2-NFkB pathway (Su et al, 2017). In another study, LPS An intriguing aspect of our findings is that despite a significant increase of IL-6 transcription in SGPL1-deficient brains, LPS stimulation was a prerequisite for the induction of TNF and IL-6 release from primary microglial cultures as well as in S1P treated BV2 microglia, suggesting that LPS-TLR4 (Toll-like receptor 4) signaling may accentuate S1P-SIPR trans activation at least in vitro.…”

Section: Discussionmentioning

confidence: 95%

“…TNF and IL‐6 were found to be the predominant cytokine signature of the primary microglia of SGPL1 fl/fl/Nes mice. In a rat model of cerebral ischemia reperfusion, S1P addition to primary microglia was found to elevate the levels of the cytokine IL‐17A (Lv, Zhang, Dai, Zhang, & Zhang, ), which was found to be mediated by the sphingosine kinase1‐TRAF2‐NFkB pathway (Su et al, ). In another study, LPS treated primary microglial cultures released elevated levels of the chemokine CXCL5 (O'Sullivan, O'Sullivan, Healy, Dev, & Sheridan, ).…”

Section: Discussionmentioning

confidence: 99%

Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Indulekha

Alam

Surendar

et al. 2019

Glia

View full text Add to dashboard Cite

Microglia mediated responses to neuronal damage in the form of neuroinflammation is a common thread propagating neuropathology. In this study, we investigated the microglial alterations occurring as a result of sphingosine 1‐phosphate (S1P) accumulation in neural cells. We evidenced increased microglial activation in the brains of neural S1P‐lyase (SGPL1) ablated mice (SGPL1fl/fl/Nes) as shown by an activated and deramified morphology and increased activation markers on microglia. In addition, an increase of pro‐inflammatory cytokines in sorted and primary cultured microglia generated from SGPL1 deficient mice was noticed. Further, we assessed autophagy, one of the major mechanisms in the brain that keeps inflammation in check. Indeed, microglial inflammation was accompanied by defective microglial autophagy in SGPL1 ablated mice. Rescuing autophagy by treatment with rapamycin was sufficient to decrease interleukin 6 (IL‐6) but not tumor necrosis factor (TNF) secretion in cultured microglia. Rapamycin mediated decrease of IL‐6 secretion suggests a particular mechanistic target of rapamycin (mTOR)‐IL‐6 link and appeared to be microglia specific. Using pharmacological inhibitors of the major receptors of S1P expressed in the microglia, we identified S1P receptor 2 (S1PR2) as the mediator of both impaired autophagy and proinflammatory effects. In line with these results, the addition of exogenous S1P to BV2 microglial cells showed similar effects as those observed in the genetic knock out of SGPL1 in the neural cells. In summary, we show a novel role of the S1P‐S1PR2 axis in the microglia of mice with neural‐targeted SGPL1 ablation and in BV2 microglial cell line exogenously treated with S1P.

show abstract

Recent advances of the function of sphingosine 1‐phosphate (S1P) receptor S1P3

Fan

Liu

Shi

et al. 2020

Journal Cellular Physiology

View full text Add to dashboard Cite

Known as a variety of sphingolipid metabolites capable of performing various biological activities, sphingosine 1-phosphate (S1P) is commonly found in platelets, red blood cells, neutrophils, lymph fluid, and blood, as well as other cells and body fluids. S1P comprises five receptors, namely, S1P1-S1P5, with the distribution of S1P receptors exhibiting tissue selectivity to some degree. S1P1, S1P2, and S1P3 are extensively expressed in a wide variety of different tissues. The expression of S1P4 is restricted to lymphoid and hematopoietic tissues, while S1P5 is primarily expressed in the nervous system. S1P3 plays an essential role in the pathophysiological processes related to inflammation, cell proliferation, cell migration, tumor invasion and metastasis, ischemia-reperfusion, tissue fibrosis, and vascular tone. In this paper, the relevant mechanism in the role of S1P3 is summarized.

show abstract

Sphk1 mediates neuroinflammation and neuronal injury via TRAF2/NF-κB pathways in activated microglia in cerebral ischemia reperfusion

Cited by 49 publications

References 34 publications

The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1

The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1

Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Recent advances of the function of sphingosine 1‐phosphate (S1P) receptor S1P3

Contact Info

Product

Resources

About