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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 ≥ 4 PRLs had higher sCD163 levels in the CSF than pwMS with ≤ 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.

Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation is gradually compartmentalized and restricted to specific tissue niches such as the lesion rim. However, the precise cell type composition of such niches, their interactions and changes between chronic active and inactive stages are incompletely understood. We used single-nucleus and spatial transcriptomics from subcortical MS and corresponding control tissues to map cell types and associated pathways to lesion and nonlesion areas. We identified niches such as perivascular spaces, the inflamed lesion rim or the lesion core that are associated with the glial scar and a cilia-forming astrocyte subtype. Focusing on the inflamed rim of chronic active lesions, we uncovered cell–cell communication events between myeloid, endothelial and glial cell types. Our results provide insight into the cellular composition, multicellular programs and intercellular communication in tissue niches along the conversion from a homeostatic to a dysfunctional state underlying lesion progression in MS. Lerma-Martin et al. generated a paired single-nucleus RNA sequencing and spatial transcriptomics dataset from subcortical multiple sclerosis lesions, identifying spatial niches and key cell interactions driving inflammation and disease progression at the lesion rim.

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

Multiple sclerosis (MS) is a prototypic chronic-inflammatory disease of the central nervous system. After initial lesion formation during active demyelination, inflammation is gradually compartmentalized and restricted to specific tissue areas such as the lesion rim in chronic-active lesions. However, the cell type-specific and spatially restricted drivers of chronic tissue damage and lesion expansion are not well understood. Here, we investigated the properties of subcortical white matter lesions by creating a cell type-specific spatial map of gene expression across various inflammatory lesion stages in MS. An integrated analysis of single-nucleus and spatial transcriptomics data enabled us to uncover patterns of glial, immune and stromal cell subtype diversity, as well as to identify cell-cell communication and signaling signatures across lesion and non-lesion tissue areas in MS. Our results provide insights into the conversion of the tissue microenvironment from a homeostatic to a pathogenic or dysfunctional state underlying lesion progression in MS. We expect that this study will help identify spatially resolved cell type-specific biomarkers and therapeutic targets for future interventional trials in MS. Competing Interest Statement J.S.R. reports funding from GSK and Sanofi and fees from Travere Therapeutics and Astex Pharmaceuticals. P.E. has received travel expenses from Bayer Health Care and is a member of the Editorial Board of the Journal of Neuroimaging. D.S. reports funding from GSK. L.S. reports research support and consultancy fees from Novartis, Roche, Bristol-Myers Squibb and Merck and filed a patent for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (WO2015166057A1).