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Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis
Annika Hofmann1, Nik Krajnc2,3,4, Assunta Dal-Bianco2,4
1Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Acta Neuropathologica
|September 16, 2023
Summary
Researchers found that myeloid cells in multiple sclerosis (MS) lesions take up iron via haptoglobin-hemoglobin, correlating with disease worsening. This CD163-mediated pathway highlights a key mechanism in MS pathology.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Iron Metabolism in CNS Disease
Background:
- Sustained inflammation in multiple sclerosis (MS) is indicated by iron-sensitive MRI, specifically paramagnetic rim lesions (PRLs).
- The precise cellular mechanisms and molecular pathways of iron uptake and metabolism in MS lesions remain unclear.
- Understanding these pathways is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the cell-type-specific pathways of iron uptake and metabolism in chronic active MS lesions.
- To correlate iron deposition in PRLs with clinical outcomes in people with MS (pwMS).
- To explore the role of the haptoglobin-hemoglobin scavenger receptor CD163 in iron handling within MS lesions.
Main Methods:
- Analysis of postmortem brain tissue from MS cases and controls using immunohistochemistry and RNA analysis for iron and immune markers.
- In vivo iron-sensitive MRI to quantify PRLs in a cohort of 98 pwMS.
- Measurement of soluble CD163 (sCD163) in cerebrospinal fluid (CSF) and haptoglobin genotyping in pwMS.
Main Results:
- Iron uptake in chronic active MS lesion rims is associated with C1QA-expressing myeloid cell (MC) subtypes.
- These MCs show upregulated CD163, HMOX1, and HAMP, and downregulated P2RY12, indicating a specific iron-handling phenotype.
- Higher CSF sCD163 levels correlate with increased PRL counts, and PRL number is associated with clinical worsening in pwMS.
- While haptoglobin (Hp) haplotypes did not influence PRL counts, Hp2 allele carriers showed higher clinical disability.
Conclusions:
- The CD163-HMOX1-HAMP axis in MCs at chronic active lesion rims suggests haptoglobin-bound hemoglobin as a primary iron source in MS.
- CSF sCD163 levels serve as a relevant biomarker for CD163-mediated iron uptake via haptoglobin-bound hemoglobin in MS.
- The Hp2 allele may confer an increased risk for clinical worsening in pwMS, warranting further investigation.
