Toll-Like Receptor 4/MyD88–Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage

Xiong, Xiao Yi; Liu, Liang; Wang, Fa Xiang; Yang, Yuan; Hao, Jun Wei; Wang, Peng Fei; Zhong, Qi; Zhou, Kai; Xiong, Ao; Zhu, Wen; Zhao, Ting; Meng, Zhao You; Wang, Yan Chun; Gong, Qiu Wen; Liao, Mao Fan; Wang, Jian; Yang, Qing

doi:10.1161/circulationaha.116.021881

Cited by 117 publications

(123 citation statements)

References 42 publications

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“…These specific genes function in efferocytosis and in the inhibition of cytokine responses (Axl), phagolysosome formation (Lamp1 and Cd63) and lipid efflux (Abcg1) (41,42). Clustering very closely were bin and TLR4 activation are critical initiators of the inflammatory response after ICH (30,(46)(47)(48)(49)(50)(51). After stimulation, bone marrowderived macrophages (BMDMs) were incubated with fluorescently labeled heat-shocked erythrocytes that externalized PtdSer ( Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang¹,

Goods²,

Askenase³

et al. 2017

Journal of Clinical Investigation

140

161

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-/-bone marrow chimeras (BMCs) at days 7 and 15 after ICH. Right: Quantification of residual hematoma volume in the WT and Ccr2 -/-BMCs. n = 11 at day 7; n = 9 at day 15. *P < 0.05 by Student's t test. (B) Cylinder test and apomorphine turning test from WT and Ccr2 -/-BMCs at day 15 after ICH. n = 6/group for cylinder test; n = 8/ group for apomorphine turning test. *P < 0.05 by Student's t test. (C) Cylinder test, neurological deficit score, and corner test in control-and anti-CCR2 antibody-treated mice at days 1 and 3 after collagenase ICH. n = 7/group. *P < 0.05 by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. (D) Top: Representative coronal sections show hematoma from control-and anti-CCR2 antibody-treated WT mice after blood injection ICH at 7 days. Bottom: Quantification of hematoma volume, n = 3/ group. *P < 0.05 versus control by Student's t test. (E) Top: Representative coronal sections show hematoma in the isotype control-and anti-CCR2 antibody-treated mice from collagenase model at day 12. Bottom: Quantification of hematoma volume. n = 8/group. *P < 0.05 versus control by Student's t test. (F) The cylinder test, neurological deficit score, and corner test in isotype control-and anti-CCR2 antibody-treated ICH mice at days 3, 5, 7, 9, and 11 after collagenase ICH surgery. n = 8/group. *P < 0.05 versus isotype control group by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. αCCR2, anti-CCR2 antibody.

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Section: Resultsmentioning

confidence: 99%

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang¹,

Goods²,

Askenase³

et al. 2017

Journal of Clinical Investigation

140

161

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“…Parabiosis was developed as described previously (19,20). Briefly, the mice were anesthetized by i.p.…”

Section: Parabiosismentioning

confidence: 99%

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

Meng

Zhao

Zhou

et al. 2017

The Journal of Immunology

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Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20−/− and A20-overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20−/− and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20−/− parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20−/− parabionts compared with A20−/− mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20−/− mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IκBα degradation and NF-κB activation were observed in A20−/− mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH.

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“…A recent meta-analysis demonstrated higher peripheral concentrations of IL-6 in patients with PD, strengthening clinical evidence that PD is accompanied by an inflammatory response [18]. During inflammation and infection, IL-6 directly regulates hepcidin expression [19]. Hepcidin plays an important role in regulating iron metabolism, and can downregulate FPN1 and alter other iron transport proteins such as transferrin receptor 1 [20].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 regulates iron-related proteins through c-Jun N-terminal kinase activation in BV2 microglial cell lines

Zhou

Xie

et al. 2017

PLoS ONE

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Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) and subsequent DA depletion in the striatum. Microglia activation and nigral iron accumulation play important roles in the pathogenesis of PD. Activated microglia show increased iron deposits. However, the relationship between microglia activation and iron accumulation remains unclear. In the present study, we aimed to determine how iron levels affect interleukin-6 (IL-6) synthesis, and the effect of IL-6 on cellular iron metabolism in BV2 microglial cells.IL-6 mRNA was up-regulated after FAC treatment for 12 h in BV2 cells. Iron regulatory protein 1 (IRP1) and divalent metal transporter 1 (DMT1) were up-regulated and iron exporter ferroportin 1 (FPN1) was down-regulated in BV2 cells after 24 h of IL-6 treatment. Phosphorylated JNK increased significantly compared to the control after BV2 cells were treated with IL-6 for 1 h. Pretreatment with SP600125 attenuated the up-regulation of IRP1 and DMT1 and down-regulation of FPN1 (compared to IL-6-treated group). These results suggest that iron load could increase IL-6 mRNA expression in BV2 cells. Further, IL-6 likely up-regulates IRP1 and DMT1 expression and down-regulates FPN1 expression in BV2 microglial cells through JNK signaling pathways.

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Toll-Like Receptor 4/MyD88–Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage

Cited by 117 publications

References 42 publications

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

Interleukin-6 regulates iron-related proteins through c-Jun N-terminal kinase activation in BV2 microglial cell lines

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