TY  - JOUR
AU  - Hofmann, Annika
AU  - Krajnc, Nik
AU  - Dal-Bianco, Assunta
AU  - Riedl, Christian J
AU  - Zrzavy, Tobias
AU  - Lerma-Martin, Celia
AU  - Kasprian, Gregor
AU  - Weber, Claudia E
AU  - Pezzini, Francesco
AU  - Leutmezer, Fritz
AU  - Rommer, Paulus
AU  - Bsteh, Gabriel
AU  - Platten, Michael
AU  - Gass, Achim
AU  - Berger, Thomas
AU  - Eisele, Philipp
AU  - Magliozzi, Roberta
AU  - Schirmer, Lucas
AU  - Hametner, Simon
TI  - Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.
JO  - Acta neuropathologica
VL  - 146
IS  - 5
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2023-01883
SP  - 707-724
PY  - 2023
N1  - 2023 Nov;146(5):707-724
AB  - In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening.
KW  - CD163 (Other)
KW  - Haptoglobin (Other)
KW  - Iron metabolism (Other)
KW  - Magnetic resonance imaging (Other)
KW  - Multiple sclerosis (Other)
KW  - Postmortem (Other)
KW  - White matter (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37715818
DO  - DOI:10.1007/s00401-023-02627-4
UR  - https://inrepo02.dkfz.de/record/282890
ER  -