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Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications
K Mehindate1, D J Sahlas, D Frankel
1Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir, Mortimer B. Davis-Jewish General Hospital, Montreal, Canada.
Abstract:
Proinflammatory cytokines, pathological iron deposition, and oxidative stress have been implicated in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). HO-1 mRNA levels and mitochondrial uptake of [(55)Fe]Cl(3)-derived iron were measured in rat astroglial cultures exposed to interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) alone or in combination with the heme oxygenase-1 (HO-1) inhibitors, tin mesoporphyrin (SnMP) or dexamthasone (DEX), or interferon beta1b (INF-beta). HO-1 expression in astrocytes was evaluated by immunohistochemical staining of spinal cord tissue derived from MS and control subjects. IL-1beta or TNF-alpha promoted sequestration of non-transferrin-derived (55)Fe by astroglial mitochondria. HO-1 inhibitors, mitochondrial permeability transition pore (MTP) blockers and antioxidants significantly attenuated cytokine-related mitochondrial iron sequestration in these cells. IFN-beta decreased HO-1 expression and mitochondrial iron sequestration in IL-1beta- and TNF-alpha-challenged astroglia. The percentage of astrocytes coexpressing HO-1 in affected spinal cord from MS patients (57.3% +/- 12.8%) was significantly greater (p < 0.05) than in normal spinal cord derived from controls subjects (15.4% +/- 8.4%). HO-1 is over-expressed in MS spinal cord astroglia and may promote mitochondrial iron deposition in MS plaques. In MS, IFN-beta may attenuate glial HO-1 gene induction and aberrant mitochondrial iron deposition accruing from exposure to proinflammatory cytokines.
Insights
Heme oxygenase-1 (HO-1) is overexpressed in multiple sclerosis (MS) astrocytes, contributing to mitochondrial iron buildup. Interferon beta-1b (IFN-beta) may reduce HO-1 expression and iron sequestration in MS.
Area of Science:
- Neuroimmunology
- Cellular pathology
- Iron metabolism
Background:
- Multiple sclerosis (MS) pathogenesis involves inflammation, iron deposition, and oxidative stress.
- Astroglia play a role in MS pathology, with potential involvement of heme oxygenase-1 (HO-1).
Purpose of the Study:
- To investigate the role of HO-1 in cytokine-induced mitochondrial iron sequestration in astrocytes.
- To determine the effect of interferon beta-1b (IFN-beta) on HO-1 expression and iron handling in MS-relevant models.
Main Methods:
- Primary rat astroglial cultures were treated with proinflammatory cytokines (IL-1beta, TNF-alpha) and HO-1 modulators (SnMP, DEX, IFN-beta).
- Mitochondrial iron uptake was measured using radioactive iron ([(55)Fe]Cl(3)).
- HO-1 expression was assessed via immunohistochemistry in spinal cord tissue from MS patients and controls.
Main Results:
- Proinflammatory cytokines induced mitochondrial iron sequestration in astrocytes.
- HO-1 inhibitors, MTP blockers, and antioxidants reduced this cytokine-induced iron uptake.
- IFN-beta decreased HO-1 expression and mitochondrial iron sequestration.
- Astrocytes in MS spinal cords showed significantly higher HO-1 coexpression compared to controls.
Conclusions:
- HO-1 is upregulated in MS spinal cord astroglia and contributes to pathological mitochondrial iron deposition.
- IFN-beta may mitigate glial HO-1 induction and iron dysregulation in MS by reducing proinflammatory cytokine effects.