Monocyte-secreted Wnt reduces the efficiency of central nervous system remyelination

TL;DR

Monocytes release Wnt proteins that hinder the regrowth of myelin in the central nervous system, offering a new target for improving CNS repair.

Contribution

The study identifies monocyte-secreted Wnt as a novel inhibitor of remyelination in the CNS.

Findings

Monocytes, not microglia, uniquely regulate remyelination by promoting differentiation but inhibiting myelin production.

Wnt signaling in monocytes is reduced in mouse models and human MS lesions, leading to improved remyelination when inhibited.

Blocking monocyte Wnt signaling increases the efficiency of CNS remyelination.

Abstract

The regeneration of myelin in the central nervous system (CNS) reinstates nerve health and function, yet its decreased efficiency with aging and progression of neurodegenerative disease contributes to axonal loss and/or degeneration. Although CNS myeloid cells have been implicated in regulating the efficiency of remyelination, the distinct contribution of blood monocytes versus that of resident microglia is unclear. Here, we reveal that monocytes have non-redundant functions compared to microglia in regulating remyelination. Using a transgenic mouse in which classical monocytes have reduced egress from bone marrow (Ccr2−/−), we demonstrate that monocytes drive the timely onset of oligodendrocyte differentiation and myelin protein expression, yet impede myelin production. Ribonucleic acid sequencing revealed a Wnt signature in wild-type mouse lesion monocytes, which was confirmed in monocytes from multiple sclerosis white matter lesions and blood. Genetic or pharmacological inhibition of Wnt release by monocytes increased remyelination. Our findings reveal monocytes to be critical regulators of remyelination and identify monocytic Wnt signaling as a promising therapeutic target to inhibit for increased efficiency of CNS regeneration.

Remyelination in the central nervous system (CNS) is influenced by myeloid cells, which includes resident microglia and infiltrating monocytes that are difficult to distinguish. This study shows that infiltrating monocytes inhibit the efficiency of remyelination, revealing their specific contribution in CNS remyelination.

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