Interleukin‐10 release from astrocytes suppresses neuronal apoptosis via the <scp>TLR</scp>2/<scp>NF</scp>κB pathway in a neonatal rat model of hypoxic‐ischemic brain damage

He, Mu; Lv, Ze Yu; Shi, Xia; Yang, Ting; Zhang, Yun; Li, Tingyu; Chen, Jie

doi:10.1111/jnc.14126

Cited by 23 publications

(15 citation statements)

References 51 publications

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“…The associations between raised IL-10 and NE severity, 39 neonatal mortality, 40,41 and early childhood NDI in NE 42 have been reported previously in several smaller studies. IL-10 is an anti-inflammatory cytokine released via a Toll-like receptor 2/nuclear factor-κBdependent pathway 43,44 following HI. 45 Whether elevated IL-10 reflects, or contributes to, severity of brain injury is unclear.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

et al. 2021

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Background Neonatal encephalopathy (NE) contributes substantially to child mortality and disability globally. We compared cytokine profiles in term Ugandan neonates with and without NE, with and without perinatal infection or inflammation and identified biomarkers predicting neonatal and early childhood outcomes. Methods In this exploratory biomarker study, serum IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF (<12 h) were compared between NE and non-NE infants with and without perinatal infection/inflammation. Neonatal (severity of NE, mortality) and early childhood (death or neurodevelopmental impairment to 2.5 years) outcomes were assessed. Predictors of outcomes were explored with multivariable linear and logistic regression and receiver-operating characteristic analyses. Results Cytokine assays on 159 NE and 157 non-NE infants were performed; data on early childhood outcomes were available for 150 and 129, respectively. NE infants had higher IL-10 (p < 0.001), higher IL-6 (p < 0.017), and lower VEGF (p < 0.001) levels. Moderate and severe NE was associated with higher IL-10 levels compared to non-NE infants (p < 0.001). Elevated IL-1α was associated with perinatal infection/inflammation (p = 0.013). Among NE infants, IL-10 predicted neonatal mortality (p = 0.01) and adverse early childhood outcome (adjusted OR 2.28, 95% CI 1.35–3.86, p = 0.002). Conclusions Our findings support a potential role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy. Impact Neonatal encephalopathy is a common cause of child death and disability globally. Inflammatory cytokines are potential biomarkers of encephalopathy severity and outcome. In this Ugandan health facility-based cohort, neonatal encephalopathy was associated with elevated serum IL-10 and IL-6, and reduced VEGF at birth. Elevated serum IL-10 within 12 h after birth predicted severity of neonatal encephalopathy, neonatal mortality, and adverse early childhood developmental outcomes, independent of perinatal infection or inflammation, and provides evidence to the contribution of the inflammatory processes. Our findings support a role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy in a sub-Saharan African cohort.

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Section: Discussionmentioning

confidence: 99%

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

et al. 2021

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“…Increment studies show that ischemia can induce cell cycle arrest or apoptotic cell death of cortical astrocytes in infarct area [28]. Ischemia-induced growth arrest of astrocytes can be overridden by inhibition of regulator of G protein signaling 2 (RGS2) and treatment with cytokine erythropoietin (EPO) [28,29], and cytokine-mediated induction of astrocyte survival early post-ischemia may contribute to neuroprotective effect [30]. Although the precise mechanism behind these effects remains unclear, these treatments may induce synchronous entry of cells into the late S phase that is associated with apoptotic resistance [28,31].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

Jiao

Chen

et al. 2020

J Neuroinflammation

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Background: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxicischemic (HI) brain injury and elucidate the underlying mechanisms of action. Methods: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia and treated with IL-33 at a dose of 0.2 μg/day i.p. for 3 days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells and cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes. Results: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 days after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. Conclusions: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

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“…Increment studies show that ischemia can induce cell-cycle arrest or apoptotic cell death of cortical astrocytes in infarct area [28]. Ischemiainduced growth arrest of astrocytes can be overridden by inhibition of regulator of G protein signaling 2 (RGS2) and treatment with cytokine erythropoietin (EPO) [28,29], and cytokine-mediated induction of astrocyte survival early post ischemia may contribute to neuroprotective effect [30]. Although the precise mechanism behind these effects remains unclear, these treatments may induce synchronous entry of cells into late S phase that is associated with apoptotic resistance [28,31].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

Jiao

Chen

et al. 2020

Preprint

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Background: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action.Methods: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia, and treated with IL-33 at a dose of 0.2 μg/day i.p. for three days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells, cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes.Results: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 d after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. Conclusions: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

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Interleukin‐10 release from astrocytes suppresses neuronal apoptosis via the TLR2/NFκB pathway in a neonatal rat model of hypoxic‐ischemic brain damage

Cited by 23 publications

References 51 publications

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

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