Astrocytic expression of the RNA regulator HuR accentuates spinal cord injury in the acute phase

Kwan, Thaddaeus; Floyd, Candace L.; Patel, J.R.; Mohaimany-Aponte, Amanda; King, Peter H.

doi:10.1016/j.neulet.2017.05.003

Cited by 11 publications

(19 citation statements)

References 32 publications

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“…It is noteworthy that astrocytes are cells of ectodermal origin, while macrophages as well as microglia are cells of hematopoietic origin. Moreover, it was previously shown that the activation of TLR4 signaling in astrocytes differs from that in myeloid cells in several major regulatory respects [26,27]. Thus, an important outcome of our studies on the molecular mechanisms of the endotoxin tolerance model for astrocytes was that an inflammatory response is not a specialized function of cells of hematopoietic origin, but rather a fundamental attribute of other cellular types.…”

Section: Discussionmentioning

confidence: 80%

Cellular Model of Endotoxin Tolerance in Astrocytes: Role of Interleukin 10 and Oxylipins

Chistyakov

Astakhova

Azbukina

et al. 2019

Cells

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A phenomenon of endotoxin tolerance where prior exposure of cells to minute amounts of lipopolysaccharide (LPS) causes them to become refractory to a subsequent high-amount endotoxin challenge is well described for innate immune cells such as monocytes/macrophages, but it is still obscure for brain cells. We exposed primary rat cortical astrocytes to a long-term low-grade concentration of LPS, followed by stimulation with a middle-grade concentration of LPS. Inflammatory markers, i.e., pro-inflammatory cytokine TNFα, inducible enzymes COX-2 and iNOS, anti-inflammatory cytokine interleukin 10 (IL-10) detected at the mRNA and protein levels reveal similarities between astrocytes and macrophages in the model, i.e., tolerance in pro-inflammatory markers and priming in IL-10. Long-term or short-term treatment with IL-10 does not change cell sensitivity for LPS, which makes doubtful its involvement in the mechanisms of cell tolerance development. Significant changes occur in the oxylipin profiles measured by UPLC-MS/MS analysis. The priming occurs in the following compounds: 11-HETE, PGD 2 , PGE 2 , cyclopentenone prostaglandins, and TXB 2 . Tolerance is observed for 12-HHT, PGF 2α , and 6-keto-PGF 1α . As far as we know, this is the first report on changes in oxylipin profiles in the endotoxin tolerance model. The data can greatly improve the understanding of oxylipins' role in inflammatory and resolution processes in the brain and mechanisms of astrocyte involvement in neuroinflammation.

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Section: Discussionmentioning

confidence: 80%

Cellular Model of Endotoxin Tolerance in Astrocytes: Role of Interleukin 10 and Oxylipins

Chistyakov

Astakhova

Azbukina

et al. 2019

Cells

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“…This correlative finding suggests that transgenic HuR in perilesional astrocytes disrupts vascular permeability through its regulation of downstream mediators such as the ones mentioned above. Interestingly, in a model of traumatic spinal cord injury in the same Tg mouse line, we also observed increased vascular permeability in HuR Tg mice compared to Wt littermates [22]. When the two studies are considered together, ectopic HuR appears to modulate common downstream pathways in two remarkably different CNS injury models [36].…”

Section: Discussionmentioning

confidence: 99%

“…A large number of inflammatory mediators increased in ischemic stroke is regulated post-transcriptionally through AREs in the 3′ UTR [4, 7, 11, 28, 32]. We have previously shown that many of these targets are positively regulated by HuR in astrocytes and microglia, including TNF-α, IL-6, IL-1β and MMP-12 [22, 25]. In the acute phase, astrocyte activation can disrupt the blood-brain barrier and/or facilitate the development of edema through the secretion of these factors [2, 6, 13, 17, 31].…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke

Ardelt

Carpenter

Iwuchukwu

et al. 2017

Neuroscience Letters

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Background and Purpose Ischemic stroke produces significant morbidity and mortality, and acute interventions are limited by short therapeutic windows. Novel approaches to neuroprotection and neurorepair are necessary. HuR is an RNA binding protein (RBP) which modulates RNA stability and translational efficiency of genes linked to ischemic stroke injury. Methods Using a transgenic (Tg) mouse model, we examined the impact of ectopic HuR expression in astrocytes on acute injury evolution after transient middle cerebral artery occlusion (tMCAO). Results HuR transgene expression was detected in astrocytes in perilesional regions and contralaterally. HuR Tg mice did not improve neurologically 72 hours after injury, whereas littermate controls did. In Tg mice, increased cerebral vascular permeability and edema were observed. Infarct volume was not affected by the presence of the transgene. Conclusions Ectopic expression of HuR in astrocytes worsens outcome after transient ischemic stroke in mice in part by increasing vasogenic cerebral edema. These findings suggest that HuR could be a therapeutic target in cerebral ischemia/reperfusion.

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“…Moreover, HMW HA decreased the production of IL-1β, IL-6, TNFα and nitric oxide in microglial cells exposed to lipopolysaccharide (LPS) [15]. It is noteworthy that microglial cells are cells of immune origin, while astrocytes have an ectodermal origin and differ from myeloid cells in several major regulatory respects [16,17]. Important to note that astrocytes have widely developed TLR signaling system, including TLR2, TLR4, TLR5, TLR3, CD44 [18,19].…”

Section: Introductionmentioning

confidence: 99%

High and Low Molecular Weight Hyaluronic Acid Differentially Influences Oxylipins Synthesis in Course of Neuroinflammation

Chistyakov

Astakhova

Azbukina

et al. 2019

IJMS

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Hyaluronic acid (HA), a major glycosaminoglycan of the extracellular matrix, has cell signaling functions that are dependent on its molecular weight. Anti-inflammatory effects for high-molecular-weight (HMW) HA and pro-inflammatory effects for low-molecular-weight (LMW) HA effects were found for various myeloid cells, including microglia. Astrocytes are cells of ectodermal origin that play a pivotal role in brain inflammation, but the link between HA with different molecular weights and an inflammatory response in these cells is not clear. We tested the effects of LMW and HMW HA in rat primary astrocytes, stimulated with Poly:IC (PIC, TLR3 agonist) and lipopolysaccharide (LPS, TLR4 agonist). Oxylipin profiles were measured by the UPLC-MS/MS analysis and metabolites HDoHEs (from docosahexaenoic acid), -HETEs, prostaglandins (from arachidonic acid), DiHOMEs and HODEs (from linoleic acid) were detected. Both, HMW and LMW HA downregulated the cyclooxygenase-mediated polyunsaturated fatty acids metabolism, LMW also reduced lipoxygenase-mediated fatty acid metabolism. Taken together, the data show that both LMW and HMW (i) influence themselves on cytokines (TNFα, IL-6, IL-10), enzymes iNOS, COX-2, and oxylipin levels in extracellular medium of cultured astrocytes, (ii) induced cellular adaptations in long-term applications, (iii) modulate TLR4- and TLR3-signaling pathways. The effects of HMW and LMW HA are predominantly revealed in TLR4– and TLR3- mediated responses, respectively.

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Astrocytic expression of the RNA regulator HuR accentuates spinal cord injury in the acute phase

Cited by 11 publications

References 32 publications

Cellular Model of Endotoxin Tolerance in Astrocytes: Role of Interleukin 10 and Oxylipins

Cellular Model of Endotoxin Tolerance in Astrocytes: Role of Interleukin 10 and Oxylipins

Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke

High and Low Molecular Weight Hyaluronic Acid Differentially Influences Oxylipins Synthesis in Course of Neuroinflammation

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