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Hypoxia inducible factor-1α mediates iron uptake which induces inflammatory response in amoeboid microglial cells in
Gurugirijha Rathnasamy1, Eng-Ang Ling1, Charanjit Kaur1
1Department of Anatomy, MD10, 4 Medical Drive, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
Abstract:
Iron accumulation occurs in tissues such as periventricular white matter (PWM) in response to hypoxic injuries, and microglial cells sequester excess iron following hypoxic exposure. As hypoxia has a role in altering the expression of proteins involved in iron regulation, this study was aimed at examining the interaction between hypoxia inducible factor (HIF)-1α and proteins involved in iron transport in microglial cells, and evaluating the mechanistic action of deferoxamine and KC7F2 (an inhibitor of HIF-1α) in iron mediated hypoxic injury. Treating the microglial cultures with KC7F2, led to decreased expression of transferrin receptor and divalent metal transporter-1. Administration of deferoxamine or KC7F2 to hypoxic microglial cells enhanced extracellular signal-regulated kinase (ERK) phosphorylation (p-ERK), but decreased the phosphorylation of p38 (p-p38). The increased p-ERK further phosphorylated the cAMP response element-binding protein (p-CREB) which in turn may have resulted in the increased mitogen activated protein kinase (MAPK) phosphatase 1 (MKP1), known to dephosphorylate MAPKs. Consistent with the decrease in p-p38, the production of pro-inflammatory cytokines TNF-α and IL-1β was reduced in hypoxic microglia treated with deferoxamine and SB 202190, an inhibitor for p38. This suggests that the anti-inflammatory effect exhibited by deferoxamine is by inhibition of p-p38 induced inflammation through the pERK-pCREB-MKP1 pathway, whereas that of KC7F2 requires further investigation. The present results suggest that HIF-1α may mediate iron accumulation in hypoxic microglia and KC7F2, similar to deferoxamine, might provide limited protection against iron induced PWMD.
Insights
Hypoxia inducible factor (HIF)-1α may drive iron buildup in microglia. Deferoxamine and KC7F2 treatments altered signaling pathways, potentially reducing inflammation and iron-induced injury in periventricular white matter (PWMD).
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Hypoxic injuries lead to iron accumulation in tissues like periventricular white matter (PWM).
- Microglia, the brain's immune cells, sequester excess iron after hypoxia.
- Hypoxia influences the expression of iron-regulating proteins, necessitating investigation into these mechanisms.
Purpose of the Study:
- To examine the interaction between hypoxia-inducible factor (HIF)-1α and iron transport proteins in microglial cells.
- To evaluate the mechanistic effects of deferoxamine and KC7F2 (a HIF-1α inhibitor) on iron-mediated hypoxic injury.
Main Methods:
- Microglial cell cultures were subjected to hypoxic conditions.
- Treatments included KC7F2 (HIF-1α inhibitor), deferoxamine, and SB 202190 (p38 inhibitor).
- Analysis involved assessing protein expression, phosphorylation (e.g., ERK, p38, CREB), and cytokine production (TNF-α, IL-1β).
Main Results:
- KC7F2 treatment decreased transferrin receptor and divalent metal transporter-1 expression.
- Deferoxamine and KC7F2 enhanced ERK phosphorylation (p-ERK) and decreased p38 phosphorylation (p-p38).
- Reduced p-p38 correlated with decreased pro-inflammatory cytokines TNF-α and IL-1β.
Conclusions:
- HIF-1α may mediate iron accumulation in hypoxic microglia.
- Deferoxamine's anti-inflammatory effect involves inhibiting p38 via the pERK-pCREB-MKP1 pathway.
- KC7F2 and deferoxamine may offer limited protection against iron-induced periventricular white matter damage (PWMD).
