Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress

Cheng, Hui-Teng; Yen, Chung‐Jen; Chang, Chen-Chih; Huang, Kuo-Tong; Chen, Kuo-Hsuan; Zhang, Rui‐Yang; Lee, Ping-Yi; Miaw, Shi‐Chuen; Huang, Jenq‐Wen; Chiang, Chih‐Kang; Wu, Mai‐Szu; Hung, Kuan‐Yu

doi:10.1016/j.bbagen.2015.09.018

Cited by 53 publications

(46 citation statements)

References 47 publications

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“…This difference in sensitivity to the high doses of Sema4A appear related to cells of higher passage number being more sensitive. Previous studies of oligodendrocytes have demonstrated that while transferrin receptor is expressed by immature oligodendrocytes, it is absent in mature myelinating oligodendrocytes and adult human brain WM (Bean et al, ; Cheng et al, ; Hulet, Menzies, & Connor, ). This finding corroborates our earlier studies demonstrating ferritin binding in WM tracts in rodents and humans (Hulet, Hess, et al, ; Hulet, Heyliger, Powers, & Connor, ; Hulet et al, ) and other studies demonstrating ferritin binding to oligodendrocytes (Chen et al, ; Han et al, ; Todorich et al, ).…”

Section: Discussionmentioning

confidence: 97%

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Chiou

Lucassen

Sather

et al. 2018

Glia

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Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H-ferritin interact through the T-cell immunoglobulin and mucin domain (Tim-2) receptor in mice. H-ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim-2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. Moreover, we also demonstrate the ability of H-ferritin to block Sema4A-mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system.

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Section: Discussionmentioning

confidence: 97%

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Chiou

Lucassen

Sather

et al. 2018

Glia

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“…That higher H-ferritin levels were associated with undetectable plasma virus but a higher quantity of CSF virus suggests that induction of H-ferritin in the CNS may be a physiological (cytoprotective) response to viral compartmentalization and replication in the CNS. HIV-induced oxidative stress is manifested by upregulation of heme-oxygenase-1 in the brain [84], and the ferroxidase activity of H-ferritin has recently been shown to mediate the antioxidant activity of heme oxygenase-1 [85]. Due to its high metabolic demands, the brain also requires a steady supply of iron in non-reactive form, for energy production as well as myelin and neurotransmitter synthesis [61, 86–88].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Patton

Wang

Hulgan

et al. 2017

Fluids Barriers CNS

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BackgroundHIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND.MethodsWe quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood–CSF-barrier.ResultsAmong 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/µL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 µg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 µg/dL in Hispanics and Whites, respectively, vs. 3.7 µg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p < 0.05), and transferrin 14% higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50% higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for QAlb and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05).ConclusionsCSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.Electronic supplementary materialThe online version of this article (doi:10.1186/s12987-017-0058-1) contains supplementary material, which is available to authorized users.

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“…Indeed, HO-1 is the inducible form of HO system, which carries out the degradation of the iron-containing molecule heme and generates free iron (Fe 2+ ), carbon monoxide and biliverdin. Free iron is quickly quenched by ferritin, which is synthesized in parallel with HO-1 induction 8 , and biliverdin is further converted into bilirubin by the activity of biliverdin reductase 9 . Overall ferritin, carbon monoxide and bilirubin exert strong antioxidant, antiapoptotic and anti-inflammatory activities 8, 10–12 .…”

Section: Introductionmentioning

confidence: 99%

Differentiation impairs Bach1 dependent HO-1 activation and increases sensitivity to oxidative stress in SH-SY5Y neuroblastoma cells

Piras

Furfaro

Brondolo

et al. 2017

Sci Rep

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Neuronal adaptation to oxidative stress is crucially important in order to prevent degenerative diseases. The role played by the Nrf2/HO-1 system in favoring cell survival of neuroblastoma (NB) cells exposed to hydrogen peroxide (H2O2) has been investigated using undifferentiated or all-trans retinoic acid (ATRA) differentiated SH-SY5Y cells. While undifferentiated cells were basically resistant to the oxidative stimulus, ATRA treatment progressively decreased cell viability in response to H2O2. HO-1 silencing decreased undifferentiated cell viability when exposed to H2O2, proving the role of HO-1 in cell survival. Conversely, ATRA differentiated cells exposed to H2O2 showed a significantly lower induction of HO-1, and only the supplementation with low doses of bilirubin (0,5–1 μM) restored viability. Moreover, the nuclear level of Bach1, repressor of HO-1 transcription, strongly decreased in undifferentiated cells exposed to oxidative stress, while did not change in ATRA differentiated cells. Furthermore, Bach1 was displaced from HO-1 promoter in undifferentiated cells exposed to H2O2, enabling the binding of Nrf2. On the contrary, in ATRA differentiated cells treated with H2O2, Bach1 displacement was impaired, preventing Nrf2 binding and limiting HO-1 transcription. In conclusion, our findings highlight the central role of Bach1 in HO-1-dependent neuronal response to oxidative stress.

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Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress

Cited by 53 publications

References 47 publications

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Differentiation impairs Bach1 dependent HO-1 activation and increases sensitivity to oxidative stress in SH-SY5Y neuroblastoma cells

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