Beyond Myelination: Possible Roles of the Immune Proteasome in Oligodendroglial Homeostasis and Dysfunction

Abstract

Oligodendroglia play a critical role in CNS homeostasis by myelinating neuronal axons in their mature stages. Dysfunction in this lineage occurs when early stage OPCs are not able to differentiate to replace dying Mature Myelinating Oligodendrocytes. Many hypotheses exist as to why de- and hypo-myelinating disorders and diseases occur. In this review, we present data to show that oligodendroglia can adopt components of the immune proteasome under inflammatory conditions. The works reviewed further reflect that these immune-component expressing oligodendroglia can in fact function as antigen presenting cells, phagocytosing foreign entities and presenting them via MHC II to activate CD4+ T cells. Additionally, we hypothesize, based on the limited literature, that the adoption of immune components by oligodendroglia may contribute to their stalled differentiation in the context of these disorders and diseases. The present review will underline: (1) Mechanisms of neuroinflammation in diseases associated with Immune Oligodendroglia; (2) the first associations between the immune proteasome and oligodendroglia and the subtle distinctions between these works; (3) the suggested functionality of these cells as it is described by current literature; and (4) the hypothesized consequences on metabolism. In doing so we aim to shed light on this fairly under-explored cell type in hopes that study of their functionality may lead to further mechanistic understanding of hypo- and de-myelinating neuroinflammatory disorders and diseases.

Involvement of inflammatory responses in the brain to the onset of major depressive disorder due to stress exposure

“…Furthermore, in brain imaging and postmortem evaluations of the human brain, patients with MDD have been found to show abnormalities in the white matter and/or oligodendrocytes (Czéh and Nagy, 2018;Vostrikov and Uranova, 2020). Interestingly, stress exposure in animal models can decrease the number of oligodendrocytes in the cortex and amygdala, indicating potential links between disturbed myelination and MDD (Liu et al, 2018a;Kokkosis et al, 2022;Madeira et al, 2022). In contrast, it has been reported that astrocytes are related to neuroinflammation, and astrocyte density in the frontal region is reduced in chronic stress conditions (Banasr et al, 2010;Hattori et al, 2017;Takarada-Iemata et al, 2018;Roboon et al, 2021).…”

Key roles of glial cells in the encephalopathy of prematurity

“…In cohorts with less severe outcomes (dWMI) and comparable models, dysmaturation/hypomyelination without cell death is more common (Billiards et al, 2008 ; Favrais et al, 2011 ; Li et al, 2018 ; Verney et al, 2012 ). Interestingly, recent work shows that oligodendrocytes themselves produce inflammatory and trophic factors which are hypothesized to participate in the inflammatory response, reviewed in (Kirby & Castelo‐Branco, 2021 ; Madeira et al, 2022 ) and even play a role in circuit formation (Buchanan et al, 2023 ). For instance, in a model of systemic‐inflammation driven EoP with diffuse WMI (Favrais et al, 2011 ), TLR3, IL‐1β, IFN‐β, chemokine ligand (Ccl) 2, and Cxcl10 are elevated in the immune‐activated oligodendrocytes, and this effect was greater in the pre‐OLs compared to the OPCs (Boccazzi et al, 2021 ).…”