Abstract
Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS-affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNγ, IL1β, and TNF, we observed, by RNA sequencing, marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell–cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease.
Highlights
We recently demonstrated that oligodendrocyte lineage cells directly participate in the neuroinflammatory response associated with experimental autoimmune encephalomyelitis (EAE), a model of Multiple sclerosis (MS), by releasing immunomodulatory factors [20]
We showed that TNFR2 acts as a suppressor of oligodendroglia-driven neuroinflammation, conferring protection in EAE
We demonstrate that TNFR2 plays a key beneficial role in keeping oligodendrocyte precursor cells (OPCs) from straying from their normal physiology, as demonstrated by the fact that, in naïve conditions, TNFR2 absence alone causes enhanced cell stress
Summary
Multiple sclerosis (MS), a chronic autoimmune neuroinflammatory disorder, is the leading cause of neurological disability in young adults [1]. One of the hallmarks of MS is oligodendrocyte death that results in the formation of demyelinating lesions within the CNS, both in the white and gray matter [2]. Active lesions, which are prevalent in the acute phase of relapsing-remitting MS (RRMS), are characterized by the presence of immune cell infiltrates and high levels of inflammatory factors, including cytokines and chemokines [3,4]. The efficacy of approved disease modifying therapies (DMT) for RRMS is due, predominantly, to their ability to reduce this immune-inflammatory burden [5]
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