CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis

Jarne Beliën, Stijn Swinnen, Robbe D’hondt, Laia Verdú de Juan, Nina Dedoncker, Patrick Matthys, Jan Bauer, Celine Vens, Sinéad Moylett and Bénédicte Dubois ()
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Jarne Beliën: KU Leuven
Stijn Swinnen: KU Leuven
Robbe D’hondt: KU Leuven
Laia Verdú de Juan: Medical University of Vienna
Nina Dedoncker: KU Leuven
Patrick Matthys: KU Leuven
Jan Bauer: Medical University of Vienna
Celine Vens: KU Leuven
Sinéad Moylett: KU Leuven
Bénédicte Dubois: KU Leuven

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Multiple sclerosis (MS) is characterized by heterogeneity in disease course and prediction of long-term outcome remains a major challenge. Here, we investigate five myeloid markers – CHIT1, CHI3L1, sTREM2, GPNMB and CCL18 – in the cerebrospinal fluid (CSF) at diagnostic lumbar puncture in a longitudinal cohort of 192 MS patients. Through mixed-effects and machine learning models, we show that CHIT1 is a robust predictor for faster disability progression. Integrative analysis of 11 CSF and 26 central nervous system (CNS) parenchyma single-cell/nucleus RNA sequencing samples reveals CHIT1 to be predominantly expressed by microglia located in active MS lesions and enriched for lipid metabolism pathways. Furthermore, we find CHIT1 expression to accompany the transition from a homeostatic towards a more activated, MS-associated cell state in microglia. Neuropathological evaluation in post-mortem tissue from 12 MS patients confirms CHIT1 production by lipid-laden phagocytes in actively demyelinating lesions, already in early disease stages. Altogether, we provide a rationale for CHIT1 as an early biomarker for faster disability progression in MS.

Date: 2024
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DOI: 10.1038/s41467-024-49312-y

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