Neuroinflammation: an oligodendrocentric view

Abstract

Chronic neuroinflammation, driven by CNS-resident astrocytes and microglia, as well as infiltration of the peripheral immune system, is an important pathologic mechanism across a range of neurologic diseases. For decades, research focused almost exclusively on how neuroinflammation impacted neuronal function; however, there is accumulating evidence that injury to the oligodendrocyte lineage is an important component for both pathologic and clinical outcomes. While oligodendrocytes are able to undergo an endogenous repair process known as remyelination, this process becomes inefficient and usually fails in the presence of sustained inflammation. The present review focuses on our current knowledge regarding activation of the innate and adaptive immune systems in the chronic demyelinating disease, multiple sclerosis, and provides evidence that sustained neuroinflammation in other neurologic conditions, such as perinatal white matter injury, traumatic brain injury, and viral infections, converges on oligodendrocyte injury. Lastly, the therapeutic potential of targeting the impact of inflammation on the oligodendrocyte lineage in these diseases is discussed.

Graphical Abstract

Introduction

Activation of the innate and adaptive immune systems within the central nervous system (CNS) initiates a cascade of events that culminates in a sustained neuroinflammatory environment, characterized by the production of cytokines, chemokines and reactive oxygen species, and leads to eventual neuronal loss (Leng and Edison, 2021). For decades, research investigating potential therapeutic mechanisms and targets have focused on either neurons or on astrocytes and microglia, two of the resident CNS glial cells. However, emerging evidence across a spectrum of neurologic disorders has unveiled injury to oligodendrocytes, the myelin-producing cells of the CNS, as an important component for both pathologic and clinical outcomes. In several diseases, demyelination and oligodendrocyte loss occurs prior to the emergence of any neuronal dysfunction, suggesting that white matter damage may be a primary driver of neurologic dysfunction. Unlike neurons, oligodendrocytes can undergo an endogenous repair process known as remyelination, which is primarily driven by the differentiation of oligodendrocyte precursor cells (OPCs) and their eventual integration as myelinating oligodendrocytes. This presents a potential therapeutic avenue whereby promoting remyelination can prevent or restore neuronal dysfunction and allow for functional recovery. This process, however, typically declines in efficiency as neurologic disease/aging progresses and is hampered by prolonged neuroinflammation. Much of what we know regarding the interaction between the oligodendrocyte lineage and inflammation has been gleaned through study of the classic demyelinating disease, multiple sclerosis (MS), which is characterized by bidirectional crosstalk between the oligodendrocyte lineage and immune system, collectively categorized as neuroimmune interactions. In this review, we will highlight our current knowledge of adaptive and innate immune system activation in MS and provide evidence that disruption of oligodendrocyte function by sustained neuroinflammation is an important determinant of functional outcomes in neurologic disorders, such as perinatal white matter injury, traumatic brain injury, and viral infections. The impact of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, on oligodendrocyte function has been discussed elsewhere (Festa et al., 2024)

The oligodendrocyte lineage

Myelin within the CNS is generated by oligodendrocytes and acts to insulate axons and facilitate rapid, efficient action potential conductance. These cells arise from a self-renewing pool of progenitor cells known as OPCs that remain proliferative, though the efficacy of this process declines during aging. Classically, it was thought that OPCs existed solely to generate myelinating oligodendrocytes; however, recent evidence has demonstrated that OPCs fulfill additional functions to modify neuronal circuitry, including synaptic strengthening, angiogenesis, axonal remodeling, engulfment of synapses, and antigen presentation (Yuen et al., 2014; Kirby et al., 2019; Auguste et al., 2022; Xiao et al., 2022). We will briefly discuss these newly described functions of OPCs in the following section.

Non-canonical roles of OPCs

In neuroinflammatory conditions, such as MS, OPCs can play a significant role in modulating the immune response. OPCs, like astrocytes and microglia, can undergo morphological alterations such as the shortening and thickening of processes (Nishiyama et al., 1999). These stereotypical changes in OPC morphology suggest the existence of distinct disease-associated cell states that emerge in response to alterations in the extracellular environment. OPCs have been found to express genes related to the innate immune response, including cytokines, chemokines, pattern recognition receptors (e.g. toll-like receptor 3; TLR3), and complement receptors (Hosokawa et al., 2003; Zhang et al., 2014; Moyon et al., 2015; Zeis et al., 2016) in response to an autoimmune- induced model of demyelination, experimental autoimmune encephalomyelitis (EAE). In EAE, mice are immunized to a myelin peptide in the presence of an adjuvant, leading to the infiltration of T cells and monocytes into the spinal cord and demyelination (Constantinescu et al., 2011). Additionally, OPCs have been found to express MHC class II proteins in both EAE mouse models and human patients with MS, indicating that disease states can cause OPCs to become antigen-processing and antigen-presenting cells (Kirby et al., 2019). Processing and presentation of antigens relies on phagocytosis, a function previously only attributed to microglia and astrocytes in the CNS; however, OPCs upregulate the phagocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) following EAE or cuprizone-mediated demyelination, suggesting a potential phagocytic role of OPCs in neuroinflammatory contexts (Fernández-Castañeda et al., 2020). This is consistent with a recently described role of OPCs to phagocytose synapses in the developing and mature visual cortex (Auguste et al., 2022; Buchanan et al., 2022). These expanded OPC functions may be hijacked following inflammatory demyelination, reducing normal roles of OPC in guiding neuronal function, thus contributing to eventual neuronal dysfunction due to synaptic loss.

Functions of mature oligodendrocytes

Besides providing a platform for saltatory conduction, oligodendrocytes perform other critical roles for neuronal health. This includes regulating neuronal excitability via modulation of potassium homeostasis (Larson et al., 2018), fine-tuning of neurotransmitter release (Roy et al., 2007; Xu et al., 2010; Maheras et al., 2018), formation of excitatory synapses (Wang et al., 2018), and clustering of voltage-gated sodium channels (Feinberg et al., 2010; Freeman et al., 2015). Oligodendrocytes provide crucial metabolic support to axons, allowing them to influence neuronal homeostasis independent of saltatory conduction via the transport of short carbon-chain metabolites, including lactate, to the periaxonal space through the monocarboxylate transporter 1 (MCT1) (Fünfschilling et al., 2012; Lee et al., 2012). Additionally, under reduced glucose conditions, oligodendrocytes can shift from normal myelin synthesis to fatty acid β-oxidation which enables them to share more glucose-derived pyruvate/lactate with the axonal compartment to support ATP generation and prevent axonal degeneration (Asadollahi et al., 2024). Based on these functions, it is apparent that any disruption to the oligodendrocyte lineage can have a functional impact on motor, cognitive, and behavioral domains within and between distinct brain regions (Foerster et al., 2019, 2024; Osanai et al., 2022; Cai et al., 2024). In particular, the oligodendrocyte lineage is vulnerable to neuroinflammatory insults generated by both the innate and adaptive immune system, much of what we have learned from MS.

Lessons learned from multiple sclerosis: neuroinflammation and the immune system

MS is a chronic, inflammatory, demyelinating, and neurodegenerative disease of the CNS which is characterized by damage and loss of myelin and oligodendrocytes. The pathological hallmarks of this disorder are focal lesions where demyelination with limited to no remyelination has occurred; these lesions are typically subdivided into three categories (Garton et al., 2024). Acute active lesions are characterized by blood-brain barrier (BBB) breakdown, infiltration of peripheral immune cells, activation of microglia and macrophages, and axonal injury. Chronic active lesions, on the other hand, contain a hypocellular and gliotic core surrounded by a rim of activated myeloid cells. Lastly, inactive lesions are sparsely cellular and are characterized by accumulation of chondroitin sulfate proteoglycans. Early in the disease, remyelination can occur, typically through the generation of new oligodendrocytes from OPCs that migrate into the demyelinated lesion (Garton et al., 2024). Interestingly, emerging data from post-mortem human tissue as well as mice demonstrate that oligodendrocytes that survive the demyelinating event can contribute to remyelination through the generation of new myelin sheaths (Duncan et al., 2018; Bacmeister et al., 2020); however, whether this occurs to a significant extent during disease is debated. Regardless, as patients age, this remyelination process becomes less efficient and eventually fails, leading to chronic demyelination and clinical disability (Filippi et al., 2018). These repeated demyelinating events, and subsequent remyelination, are driven by immune-glia interactions with the adaptive immune system via autoimmunity driving the initial “hit” of oligodendrocyte loss and the innate system contributing to persistent neuroinflammation that limits functional recovery. The pathological cascades underlying MS are reviewed in detail elsewhere (see (Filippi et al., 2018; Reich et al., 2018; Garton et al., 2024)) but we will briefly introduce them here to provide a framework to examine other neurologic conditions. For the purpose of this review, we will focus on the most common form of MS, relapse-remitting, which is characterized by episodic relapses; the pathophysiology of progressive MS is covered extensively elsewhere (Faissner et al., 2019; Blok et al., 2023).

The principal mediators underlying demyelination in relapse-remitting MS are aberrantly activated proinflammatory, CNS-specific effector CD8+ and CD4+ T cells, which traffic bidirectionally into the CNS parenchyma via BBB damage and a recently (re)discovered lymphatic drainage system within the CNS, glymphatics (Louveau et al., 2015; Filippi et al., 2018). Both T cell populations have been found in MS lesions with CD4s more concentrated in the perivascular cuff while CD8s are more widely distributed within the parenchyma (Reich et al., 2018). One potential cause of aberrant effector T cell activation is dysregulation of regulatory T (T_reg) cells that are necessary to restrict the autoreactive T cell population, specifically decreased expression of forkhead box protein 3 (FOXP3), which is critical for the initiation of a transcriptional program to suppress effector T-cell responses (Hori et al., 2003; Venken et al., 2008; Frisullo et al., 2009). It is hypothesized that a CNS antigen-specific immune activation occurs first in the periphery and then is transferred to the previously unaffected CNS (Wucherpfennig and Strominger, 2004; Hemmer et al., 2015). From there, T and B cells invade into the brain parenchyma, where CD4+ T cells locally release cytokines that disrupt astrocytic and oligodendroglial homeostasis (Hemmer et al., 2015). An alternately proposed hypothesis (inside-out theory) is that an initiating event occurs within the CNS that in turn results in the activation of resident microglia and secondary recruitment of peripheral adaptive and innate immune cells (Henderson et al., 2009). Regardless, damage to myelin itself does not appear to be sufficient to elicit a T or B cell response and T cells reactive to myelin antigens have been found in individuals without MS, suggesting that these cells are dysfunctional or that other immune factors are at play (Hemmer et al., 2015). In support of this, myelin-reactive T cells from MS patients are more proinflammatory, while those from healthy controls secrete more of the immunomodulatory cytokine interleukin 10 (IL-10) (Cao et al., 2015). Additionally, there is accumulating evidence that B cells, the antibody producing cells of the immune system, directly contribute to the development of MS and subsequent demyelination. The aberrant activation of the peripheral immune system, and its subsequent trafficking into the CNS, initiates a neuroinflammatory cascade that results in loss of oligodendrocytes and eventual axonal degeneration.

The cells speculated to induce direct damage to oligodendrocytes, and thus demyelination, include interleukin 17 (IL-17), granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing CD4+ and CD8+ T cells, and interferon gamma (IFNγ)-secreting CD4+ T cells (Kebir et al., 2007; Rasouli et al., 2015; van Langelaar et al., 2018). These cells not only directly destroy oligodendrocytes and myelin, but they can also contribute indirectly via activation of the innate immune system, including macrophages and microglia (Filippi et al., 2018). In vitro, IFNγ acts directly on OPCs, reducing proliferation, differentiation, and myelin production; however, its impact on OPCs in vivo is not entirely clear (Saraswat et al., 2021; Chen et al., 2023). Other cytokines implicated in oligodendrocyte injury include IL-17, which blocks OPC differentiation and enhances inflammation through Notch-1 induction, and tumor necrosis factor α (TNFα), which upon binding to tumor necrosis factor receptor 1 (TNFR1) promotes FAS-mediated apoptosis of oligodendrocytes (Hövelmeyer et al., 2005; Wang et al., 2017). Patients with MS harbor unique antibodies in their cerebrospinal fluid (CSF) suggesting that the antibody-producing properties of B cells are important in MS lesions. These antibodies, mainly immunoglobulin G (IgG) and to a lesser extent immunoglobulin M (IgM), are also found in a majority of active, chronic active, and inactive lesions (Sádaba et al., 2012). However, reduction in relapse rates associated with B cell depletion therapies, such as anti-CD20 antibodies, are associated with little to no changes in CSF immunoglobulin levels, suggesting an antibody-independent role of B cells (Monson et al., 2005; Cross et al., 2006). B cells from MS patients produce a greater proportion of pro-inflammatory cytokines, including interleukin 6 (IL-6), GM-CSF, and TNFα, while being deficient in regulatory cytokines like IL-10 compared to B cells from healthy controls (Duddy et al., 2007). These cells also drive the autoproliferation of brain-homing T cells and contribute to the formation of ectopic lymphoid aggregates in the meninges; the abundance of these aggregates correlates with the amount and size of cortical lesions, degree of neurodegeneration in the cortex, and severity of disability (Aloisi and Pujol-Borrell, 2006; Magliozzi et al., 2007; Comi et al., 2021).

Cells of the innate immune system are activated and recruited to demyelinating lesions by sensing released myelin debris within the extracellular space. This myelin debris, when not taken up by macrophages or microglia, can directly inhibit OPC differentiation and thus prevent remyelination (Baer et al., 2009). Therefore, activation of microglia and macrophages can be beneficial as they work to remove debris and encourage regeneration. However, excessive phagocytosis can transform microglia into a pro-inflammatory subtype that can contribute to sustained neuroinflammation (Hou et al., 2022). Single-nuclei RNA sequencing (snRNA-seq) of microglia from the edge of chronic active MS lesions uncovered a subtype of microglia called “microglia inflamed in MS” or MIMS that are characterized by elevations in C1Q, ferritin heavy chain (FTH1), CD68, and other iron-regulatory genes (Absinta et al., 2021). Additionally, when compared to microglia from secondary demyelination cases, MS microglia have increases in FTH1, signal induced proliferation associated 1 like 1 (SIPA1L1), and acyl-CoA synthetase long chain family member 1 (ACSL1) suggesting that there are disease-specific microglial phenotypes that can drive remyelination failure. These genes are associated with iron sequestration, excitatory synapses, and fatty acid breakdown, respectively, suggesting that microglia in MS exist in a potentially hyper-phagocytic state. In addition to being activated by myelin debris, pro-inflammatory microglia in MS are induced via other secreted proteins. Fibrinogen, a glycoprotein complex in the blood that is released after BBB disruption, directly signals through CD11b on myeloid lineage cells and induces oxidative stress pathways, redox regulation and type 1 IFN gene families (Davalos et al., 2012; Mendiola et al., 2023). Signaling of the complement component C3a onto the C3a receptor on microglia leads to upregulation of hypoxia-inducible factor 1α (HIF-1α) and eventual depletion of ATP stores and metabolic impairment (Gedam et al., 2023). C3aR activation can exhibit biphasic effects on microglial phagocytosis; short-term stimulation promotes phagocytosis while chronic activation inhibits phagocytosis (Lian et al., 2016).

Astrocytes are not classically considered part of the innate immune system; however, they are able to respond to injury, become reactive, and phagocytose myelin debris (Camargo et al., 2017; Sofroniew, 2020). In both MS and EAE, single cell profiling of astrocytes showed that they decrease expression of the antioxidant regulator, nuclear factor erythroid 2-related factor (NRF2), and upregulate MAFG, a transcription factor involved in pro-inflammatory transcriptional profiles (Wheeler et al., 2020). The pro-inflammatory cytokines, IL-1β and TNFα, can induce phosphorylation of the endoplasmic reticulum (ER) stress sensor, inositol-requiring enzyme 1 (IRE1), resulting in the full translation of X-box binding protein 1 (XBP1) and a shift in a subset of astrocytes towards pathogenicity in MS (Wheeler et al., 2019; Clark et al., 2023). In MS, as seen with microglia, astrocytes can adopt both beneficial, through the secretion of factors that promote OPC proliferation and differentiation, and deleterious roles, via molecules that inhibit the remyelination process (e.g. components of the extracellular matrix and inhibitory growth factors (Fischer et al., 2014; Hammond et al., 2014; Lindner et al., 2015). Astrocyte activation is also the result of crosstalk with microglia, whereby the secretion of the cytokines IL-1α, TNFα, and C1q from microglia leads to the emergence of an astrocytic phenotype that increases complement production (Liddelow et al., 2017). Indeed astrocytic C3 has been observed in active MS lesions (Absinta et al., 2021). Therefore, microglia and astrocytes act as partners in regulating the inflammatory response during demyelination and remyelination and can influence OPC and oligodendrocyte function.

Lastly, as mentioned earlier, OPCs can themselves adopt an immunomodulatory phenotype in both MS and EAE, potentially through IFNγ and particularly in the presence of IL-17 or TNFα (Kirby and Castelo-Branco, 2021). These transcriptionally distinct cells express genes related to the innate immune response, including TLR3 and the Serpina family (Falcão et al., 2018; Kirby et al., 2019). In turn, OPCs can amplify neuroinflammation. Selective deletion of ACT1, a component of the IL-17R signaling cascade, in PDGFRα+ OPCs significantly reduced EAE severity, highlighting a role of OPCs in perpetuating inflammatory IL-17 signaling (Kang et al., 2013). Surprisingly, a recent study demonstrated that depletion of OPCs in the acute phase of EAE improved clinical scores and reduced demyelination through a reduction in the trafficking of T and IL-17+ Th17 cells into the spinal cord. The mechanism by which OPCs promote peripheral immune cell infiltration is not currently known (Ohashi et al., 2024). This cellular heterogeneity of the oligodendrocyte lineage in MS is not limited to OPCs; distinct subpopulations of mature oligodendrocytes emerge in both rodent models of MS (EAE) and post-mortem human samples. Similar to OPCs, oligodendrocytes within lesions upregulate expression of MHC class I and class II genes, as well as the Serpin3a family (Falcão et al., 2018; Pandey et al., 2022). In another study, disease-associated oligodendrocytes expressed GPR37, a receptor known to inhibit oligodendrocyte differentiation and myelination via binding to prosaposin (PSAP) which is upregulated on disease-associated astrocytes in EAE and MS samples (Kukanja et al., 2024). Additionally, oligodendrocytes with gray matter signatures (e.g. OPALIN) were found within WM damaged regions, indicating that these GM-enriched oligodendrocytes may play a role in lesion repair or that signaling that determines oligodendrocyte identities is disturbed in active MS lesions (Kukanja et al., 2024). Even in normal appearing white matter (NAWM) in MS post-mortem samples, snRNA-seq revealed decreases in cells that were classified as “intermediate” oligodendrocytes, adding evidence to the concept that NAWM has global changes that may reflect a propensity for demyelination or remyelination (Jäkel et al., 2019).

The interplay between the innate and adaptive immune systems can have profound effects on OPC and oligodendrocyte function and, in turn, neuronal circuitry function in both acute and chronic settings. Thus, understanding how neuroinflammation in other disease and injury contexts impacts myelin may provide new insights into pathophysiological mechanisms and generate new therapeutic opportunities for multiple CNS conditions.

Impact of neuroinflammation on white matter

The extensive work investigating the intersection between the immune system and neuroinflammation in MS has provided a lens through which we can study disorders that have recently been shown to have myelin impairment. As in MS, the neuroinflammation that characterizes these diseases exists on a continuum from acute to chronic, and both adaptive and innate immunity play roles in the effects on myelin. However, in contrast to MS, where the initial loss of oligodendrocytes is driven via autoimmunity, other neurologic disorders, with some exceptions, are characterized by impairment of oligodendrocyte maintenance and function driven by loss of trophic support from astrocytes and activation of adaptive and innate immune cells (Figure 1). We will explore these functions in several different conditions where persistent neuroinflammation drives oligodendrocyte injury, including perinatal white matter injury, traumatic brain injury, and viral infections.

Figure 1. Comparison of oligodendrocyte injury in multiple sclerosis and diseases with persistent neuroinflammation.

a) During autoimmune demyelination (e.g. multiple sclerosis), oligodendrocyte loss is initially mediated primarily by the influx of adaptative immune cells (Th1 & Th17) that release inflammatory cytokines that directly cause myelin loss. Additionally, these mediators, along with myelin lipids, activate microglia/macrophages and astrocytes within the CNS. These cells have been shown to both promote and inhibit OPC differentiation and remyelination. This ultimately results in neuronal degeneration and functional decline. b) In perinatal white matter injury (WMI), a series of inflammatory and hypoxic-ischemic insults occur to the developing brain that occurs during a critical window of oligodendrocyte vulnerability. There is an increase in “reactive” astrocyte subtypes, which are associated with cytokine release, prostaglandin E2 (PGE2) secretion, and decreased glutamate buffering. Microglia express galectin-3, which serves as a chemoattractant for other immune cells, and they contribute to the inflammatory environment through the release of proinflammatory factors (e.g. cytokines, follistatin, FasL). Trafficking of T cells through the developing blood-brain barrier may also secrete factors that inhibit OPC maturation. c) Physical trauma to the brain causes direct injury to myelin, which induces oligodendrocyte cell death and the release of myelin debris into the extracellular milieu. This myelin debris can promote the activation of autoreactive T cells and the generation of autoantibodies. Myelin debris can also be phagocytosed by microglia and astrocytes, generating proinflammatory subtypes of these cells. Excess glutamate and cytokines induce an immunomodulatory phenotype in OPCs, inhibits oligodendrocyte maturation, and activates the ISR and UPR within surviving oligodendrocytes. d) HIV infects microglia and brain-associataed macrophages. These cells can activate astrocytes and, together, they secrete cytokines, reactive oxygen species (ROS), and glutamate. This leads to ISR activation, lysosomal de-acidification, and downregulation of the essential myelin gene, Myrf in OPCs and a blockade of oligodendrocyte differentiation. ARVs used to treat HIV also inhibit oligodendrocyte maturation through these cellular stress pathways. SARS-CoV2, on the other hand, has been shown to decrease OPCs, mature oligodendrocytes, and OPALIN+ oligodendrocytes, potentially through WAM and DAM microgia. Autoimmunity may also play a role as activated T cells and expansion of unique T cell clones were found in the CSF but not the blood, suggesting a compartmentalized response to a CNS antigen. Created with https://BioRender.com/m48z089.

Perinatal white matter injury

Perinatal white matter injury (WMI) is the most common cause of long-term neurologic morbidity in infants who are born pre-term (Volpe, 2019). It results from a series of inflammatory and hypoxic-ischemic insults to the developing brain during the critical window of oligodendrocyte vulnerability, typically between 23 and 32-weeks of gestation, that precedes the onset of myelination. Subsequently, the decline in risk for WMI coincides with the onset of a wave of OPC differentiation that initiates myelination in the cerebral white matter (Back and Rosenberg, 2014). Neuropathologically, perinatal WMI is characterized by astrocyte and microglia reactivity, infiltration of peripheral T and B cells, and myelination defects in periventricular white matter (Volpe, 2019). These myelination defects arise from several detrimental events that block oligodendrocyte maturation, including exposure to pro-inflammatory mediators from immune cells, reduction in insulin-like growth factor 1 (IGF1) production by microglia, and upregulation of bone morphogenetic protein (BMP) that directly inhibit OPC differentiation (Reid et al., 2012; Bokobza et al., 2023).

Impact of astrocytes on the oligodendrocyte lineage in perinatal WMI

Astrocyte reactivity is readily observed In both rodent models and post-mortem human tissue. These reactive changes include the release of pro-inflammatory cytokines, specifically TNFα and IL-1β, which as observed in MS, leads to inhibition of oligodendrocyte differentiation as well as thinner myelin sheaths and a reduction in the number of myelinated axons (Reid et al., 2012; Deng et al., 2014). While upregulation of the master transcriptional regulator HIF1α is seen in microglia in MS, it is most prominently seen in neurons and astrocytes in hypoxic-ischemic injury though the timing is different. In neurons, HIF1α is increased as early as 24 hours post injury, while in astrocytes, there is a delayed response that peaks at seven days (Wang et al., 2022a). This delayed upregulation is involved in glial scar formation and eventual arrested oligodendrocyte maturation and impaired myelination. Intriguingly, pharmacologically inhibiting delayed HIF1α expression is able to prevent astrocytic reactivity and ameliorate hypomyelination (Wang et al., 2022a). One critical role of astrocytes is to maintain appropriate levels of glutamate in the extracellular space; failure to do so can result in excitotoxic death. The timing of expression of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-d-aspartic acid receptors (NMDARs) on OPCs during white matter development coincides with the window of heightened susceptibility to perinatal WMI, suggesting that glutamate toxicity may be an important driver of hypomyelination (Jantzie et al., 2013; Spitzer et al., 2019). Taken together, reactive astrocytes secrete deleterious substances and fail to sufficiently buffer glutamate which converges on OPCs to restrict their differentiation and induce hypomyelination.

Like MS, perinatal WMI can induce disease-specific subsets of astrocytes that contribute to developmental hypomyelination. These reactive subtypes can upregulate cyclooxygenase-2 (COX2) expression and secrete prostaglandin E2 (PGE2) that can directly inhibit OPC maturation by binding to the prostaglandin E2 receptor 1 (EP1) (Shiow et al., 2017). COX2-PGE2 signaling can be targeted via administration of a COX2 inhibitor that preserves myelination and attenuates cognitive impairment (Shiow et al., 2017). The generation of neuroinflammatory reactive astrocytes appears to depend on the secretion of the inflammatory cytokines TNFα, IL-1α, and C1q, most likely from microglia, as genetic deletion of these three mediators improved myelination and prevented the formation of this astrocyte substate (Renz et al., 2024). It is important to note that only about 30–50% of astrocytes in the white matter regions examined expressed C3, a marker for this cell subtype, and may not be the only important substate underlying myelination defects in perinatal WMI.

Impact of microglia on the oligodendrocyte lineage in perinatal WMI

Microglia in the white matter are highly activated during developmental myelination and exist in a more immune-vigilant state compared to gray matter microglia, indicating a heightened sensitivity to infection or damage (Grabert et al., 2016). In the CSF of preterm infants, there is an initial and sustained pro-inflammatory response characterized by complement 5a (C5a), IL-9, Fas ligand (FasL), and follistatin expression (Boardman et al., 2018). Follistatin, in particular, is of interest as it is known to inhibit the actions of activin-A, which controls oligodendrocyte differentiation and myelin maturation during development (Dillenburg et al., 2018). Follistatin levels are increased through IL-1β, a product of the proinflammatory molecular complex NLRR family pyrin domain containing 3 (NLRP3) inflammasome (Holloway et al., 2021). These activated microglia express markers including major histocompatibility complex (MHC) class I and II molecules, C3R, and isolectin B4 (McRae et al., 1995; Tahraoui et al., 2001). In an hypoxic-ischemic mouse model, there is demonstrated increase in CD11b+/CD86+ (classic activation) microglia during the first day after injury (Erkenstam et al., 2016). Interestingly, there was a significant population of microglia that expressed neither CD86 or CD206 (alternative activation) but expressed high levels of the immunomodulatory factor galectin-3, which may be important for attracting cells to the site of injury; in support of this, administration of recombinant galectin-3 ameliorates cognitive deficits and drives remyelination after perinatal WMI (Wang et al., 2022b). Transcriptomics of microglia in a mouse model of encephalopathy of prematurity and human preterm-born infants revealed dysregulation of Wnt/β-catenin signaling, including receptors, ligands, and intracellular signaling components (Van Steenwinckel et al., 2019). The resulting microglial phenotype drives hypomyelination and specifically activating the Wnt/β-catenin using a microglia-specific targeting nanocarrier prevents pro-inflammatory microglia activation and white matter injury (Van Steenwinckel et al., 2019).

Peripheral immunity on the oligodendrocyte lineage in perinatal WMI

The data regarding the role of peripheral T and B cells are conflicting. These cells have been observed the brains of mouse models of perinatal WMI, as well as human preterm infants (Nazmi et al., 2018). In mature lymphocyte-deficient Rag1^−/− mice, which lack T and B cells, there was a significant reduction in hypoxic-ischemic WMI in the white matter but not the gray matter (Nazmi et al., 2018). On the other hand, a different study that depleted peripheral T cells via a sphingosine-1-phosphate receptor agonist, FTY720, found that this loss of peripheral T cells exacerbated hypoxic-ischemic WMI (Herz et al., 2018). A reduction in T lymphocytes, and particularly regulatory T cells, coincides with increased infiltration of innate immune cells, chiefly neutrophils and inflammatory macrophages (Herz et al., 2018). As in MS, T cell release of pro-inflammatory cytokines, such as IL-1β, TNFα, and IFNγ, in perinatal WMI can inhibit oligodendrocyte maturation directly. Cytokine release leads to increased oxidative stress, exacerbated in OPCs by low glutathione levels, and increased glutamate excitoxicity, both of which inhibit oligodendrocyte maturation and myelination (French et al., 2009; Verney et al., 2012; Al-Griw et al., 2021). Even overexpression of anti-inflammatory cytokines, such as IL-4, can cause a lack of developmental myelination, as shown in experimental models, suggesting that a tight regulation of these factors is necessary for proper developmental myelination (Zanno et al., 2019). Thus, a balance is needed between appropriate immune cell infiltration and activation during normal development, and this is disrupted in hypoxic-ischemic perinatal white matter injury.

Traumatic brain injury

Traumatic brain injury (TBI) is no longer considered an isolated event but a complex ongoing condition that becomes a chronic burden. A single moderate to severe TBI can lead to persistent injury to white matter axons and chronic brain atrophy associated with poor patient outcomes (Armstrong et al., 2024). Magnetic resonance imaging (MRI) studies utilizing diffusion tensor imaging (DTI) demonstrates that TBI is a disorder of brain connectivity with symptom expression related to slow information processing being the most prevalent impairment and with the strongest overall relationship with deficits in daily function (Sharp et al., 2011; Hayes et al., 2016; Bryant et al., 2023). A majority of the axon and oligodendrocyte damage is not due to the immediate mechanical dissociation but rather is associated with secondary injury processes (Newcombe et al., 2022). Neuropathologically, traumatic axonal injury in the white matter appears in a characteristic pattern of damaged axons dispersed among adjacent intact axons (Mierzwa et al., 2015; Song et al., 2022a). This injury to the white matter is associated with decreases in mature oligodendrocyte number, specifically via apoptosis, in classic white matter tracts such as the corpus callosum, fimbria, and external capsule (Flygt et al., 2013). This reduction in oligodendrocyte number is maintained for up to two weeks post-injury with ongoing apoptosis in regions distal to the site of injury after this time (Dent et al., 2015). As in MS, OPCs proliferate in response to the loss of myelin as early as two days post-injury, with a peak at one week, and continues for up to three months (Dent et al., 2015). Both OPCs and oligodendrocytes can adopt an immune-like cell state, including evidence for an interferon response and transcriptional activation of MHC class I and II. Furthermore, the activation of the innate immune response is linked to transcriptional activation of endogenous retroviruses within OPCs and oligodendrocytes, demonstrating that the oligodendrocyte lineage itself is involved in neuroinflammation following TBI (Garza et al., 2023). In mouse models, long myelin outfoldings of excess compact myelin have been observed to extend from a subpopulation of both heathy and degenerated axons, though it is unclear why these outfoldings occur (Mierzwa et al., 2015; Alexandris et al., 2023). Within oligodendrocytes, activation of the integrated stress response (ISR) and unfolded protein response (UPR), is observed hours post-injury (Fan et al., 2023). While acute activation of these pathways is beneficial to resolve cellular stress, chronic activation becomes maladaptive and contributes to white matter injury, including myelin thinning (Wu et al., 2020; Zhou et al., 2024).

Impact of astrocytes on the oligodendrocyte lineage in TBI

Astrogliosis, including activation and proliferation, has been widely documented after a range of TBI severities (Mira et al., 2021). In a closed-head injury, astrocytes lose vital homeostatic functions such as electrolyte buffering, glutamate uptake, and perivascular flux; additionally, they also participate in the formation of the glial scar barrier in response to penetrating injuries (Myer et al., 2006; Escartin et al., 2021). Astrocytes at the lesion site derive not only from old pre-existing astrocytes but also from polydendrocytes, indicating that astrocyte generation from progenitors occurs early after TBI (Nishiyama et al., 2009; Kim et al., 2012). Astrocytes express two major glutamate transporters, excitatory amino acid transporter 1 (EAAT1/GLAST) and 2 (EAAT2/GLT-1), and these are decreased in postmortem human tissue from TBI patients, which contributes to impaired glutamate buffering and eventual excitotoxicity, directly impacting OPC maturation (van Landeghem et al., 2006). The injury-induced inflammatory response after TBI is triggered by the release of alarmins which recruit immune cells to the site of injury. Interleukin-33 (IL-33), a nuclear alarmin, is primarily produced by astrocytes and acts on the microglial/macrophage ST2 receptor to recruit these cells to the site of injury (Wicher et al., 2017). Interestingly, IL-33 induces the transcription of myelin genes in vitro, and downregulation of IL-33 in OPCs impairs differentiation (Natarajan et al., 2016; Sung et al., 2019). However, despite the beneficial role of IL-33 on OPCs, there is an ongoing blockade of oligodendrocyte maturation that is driven by other deleterious processes stemming from astrocyte dysfunction. Astrocytes can also adopt a phagocytic phenotype at sites of acute myelin breakdown after TBI which occurs through LRP1, the same receptor upregulated by OPCs after a demyelinating insult in rodents (Ponath et al., 2017). Phagocytosis of myelin debris results in astroglial activation of NF-κB and release of chemokines that promote a neuroinflammatory environment and is sufficient to recruit peripheral Th1 CD4+ T cells into the CNS (Ponath et al., 2017). Astrocytes contribute to spreading of secondary damage following TBI through increased activity of connexin-43 (Cx43) channels (Rovegno et al., 2015). Astrocytic Cx43 can form hemichannels with connexin-47 (Cx47) on oligodendrocytes promoting direct intercellular communication and regulating myelination (Fasciani et al., 2018). Interestingly, conditional deletion of astrocytic Cx43 improves remyelination after lysolecithin demyelination suggesting that Cx43, in the context of TBI, may be a key molecular mediator of oligodendrocyte injury (Li et al., 2020). Therefore, astrocytes, either through secretion of inflammatory mediators or cell-to-cell junctions, directly contribute to myelin loss and reduced OPC differentiation in TBI long after the initial physical trauma has resolved.

Distinct functional and regional astrocytic substates exist after TBI. In a closed-head injury model, there is a robust induction in pan-reactive neurotoxic astrocytes for up to three weeks after insult; additionally, there is also an upregulation of protective phenotypes (Jacquens et al., 2024). A single-cell RNA sequencing (scRNA-seq) study observed astrocyte activation in the cortex and hippocampus after TBI (Xing et al., 2022). Pathway enrichment analysis revealed that autophagy-related pathways were activated in astrocytes from both brain regions, while inflammatory pathways were more significantly enriched in astrocytes from the hippocampus (Xing et al., 2022). Abnormal reactivity of astrocytes typically is thought to hinder long-term tissue repair and regeneration; however, it is also critical to limit the spread of inflammation. Programmed death ligand 1 (PD-L1)-expressing astrocytes act as gatekeepers to control TBI-related neuroimmune and neuroinflammatory responses and form a dense zone around the TBI lesion (Gao et al., 2022). When PD-L1 signaling is blocked, there is increased infiltration of inflammatory Ly-6C^High monocytes/macrophages but not tissue repairing Ly-6C^LowF4/80+ cells and that are associated with worsened TBI outcomes in mice (Gao et al., 2022). Taken together, these altered astrocyte reactivity substates initially work to limit the spread of neuroinflammation; however, their persistence leads to significant impairment of OPC maturation and remyelination failure.

Impact of microglia on the oligodendrocyte lineage in TBI

In response to TBI, microglia quickly gain proinflammatory and phagocytic properties via the release of danger-associated molecular patterns (DAMPs) that are associated with ongoing oligodendrocyte damage in chronic white matter degeneration (Mira et al., 2021). Markers of microglial activation, such as CD68 and MHC-II, and chemokine expression, including CXCL10, CXCL11, and CXCL6, increase as early as three hours post TBI; subsequently, inflammatory cytokines, including IFNγ, IL-4, and IL-10, in microglia exhibit a biphasic temporal expression (Israelsson et al., 2008; Izzy et al., 2019). However, another study found that expression of interferon pathways in microglia were not significantly altered and instead other inflammatory pathways such as IL-18 signaling, neutrophil degranulation, and NOD-like receptor signaling were upregulated (Xing et al., 2022). Similar to perinatal WMI, microglial NLRP3 inflammasome activation is observed early post-TBI, contributing to increased secretion of IL-1β and pyroptotic oligodendrocyte cell death (Lee et al., 2018, 2019). Neutralization of IL-1β attenuates microglial reactivity/morphology and oligodendrocyte loss when administrated immediately after injury; however, there were no changes in OPC proliferation (Flygt et al., 2018). These findings suggest that IL-1β is an important inflammatory mediator for both early microglia activation and oligodendrocyte death. Rather than directly neutralizing inflammatory cytokines, another potential therapeutic target is the Na⁺/H⁺ exchanger 1 (NHE1) on microglia. This protein is an essential microglial pH regulatory protein that maintains the optimal alkaline intracellular pH needed for sustained activation of NADPH oxidase and cytokine release (Song et al., 2022b). Deletion or inhibition of NHE1 increased anti-inflammatory, and subsequently decreased inflammatory, microglial phenotypes and accelerated oligodendrocyte regeneration during the chronic phase of TBI (Song et al., 2022b). Taken together, while microglia are essential for the removal of myelin debris following the initial injury, the chronic activation of these cells directly inhibit oligodendrocyte repair primarily through cytokine release.

Peripheral immune system in TBI

Physical trauma to the brain leads to disruption of the BBB and results in the exposure of brain-derived antigens, including myelin, which promotes the activation of autoreactive T cells and generation of autoantibodies. Autoreactive antibodies/lymphocytes specific to myelin antigens, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), are increased in the CSF and serum of TBI patients (Raad et al., 2014). However, unlike MS, several studies have demonstrated that these CD4+ CD25+ Treg cells may actually be protective by facilitating the removal of myelin debris at the lesion site (Kipnis et al., 2002; Daglas et al., 2019). While a subset of Treg cells have been shown to be beneficial, acute infiltration of CD3+ and Th1 CD4+ cells, driven by CXCL10 release from microglia, into the brain parenchyma is a contributing factor to poor recovery (Ndode-Ekane et al., 2018; Sen et al., 2020). Additionally, IL-17 expressing CD4+ T cells, impair OPC proliferation and increase the expression of MHC-II on OPCs via cell-to-cell contact (Shumilov et al., 2024). This trafficking of CD4+ T cells is preceded by a protracted CD8+ T cell expressing granzyme B response that is associated with myelin pathology (Daglas et al., 2019). Interestingly, depletion of CD8+ T cells, but not CD4+ T cells, significantly improved myelin vascularization and produced a neuroprotective immunological shift towards Th2/Th17 T cells (Daglas et al., 2019). These findings highlight the dual role of T cells in TBI where they can either play a protective or deleterious role on the oligodendrocyte lineage depending on T cell subtype.

Viral infections

The SARS-CoV-2 (Covid-19) pandemic has reignited interest in how viral infections can impact the CNS, even after the acute initial infection has resolved; damage can occur by direct infection of the CNS and/or the host response to the pathogen. As seen in TBI and perinatal WMI, OPCs and oligodendrocytes are particularly vulnerable to the neuroinflammation driven by these viral-mediated insults, despite these cells typically not being infected by viruses. Additionally, evidence from the well-established viral rodent models of MS, including Theiler’s murine encephalomyelitis virus (TMEV) and strain JHM of murine hepatitis virus (MHV), demonstrate that viruses that do not directly infect the oligodendrocyte lineage can induce robust oligodendrocyte injury and demyelination (Bender and Weiss, 2010; Tsunoda and Fujinami, 2010). Here, we will discuss two different types of viral infections, one that results in a viral reservoir in the CNS (human immunodeficiency virus) and another that does not (SARS-CoV2), with a focus on the cellular mechanisms of neuroinflammation and oligodendrocyte injury linked to these viruses rather than cell-type specific effects as evidence is still emerging regarding the contribution of the innate and adaptive immune systems.

Human immunodeficiency virus

Neurological symptoms associated with human immunodeficiency virus (HIV) infection affect approximately 20–50% of people living with HIV (PLWH) despite suppressive antiretroviral therapy (ART) that is able to render peripheral viral load to undetectable levels (Saylor et al., 2016). While ART has been able to dramatically shift the clinical manifestations of HIV-associated neurocognitive disorder (HAND) with a significant reduction in the most severe form, HIV-associated dementia (HAD), milder forms of the disease account for the continued prevalence of HAND (Heaton et al., 2010). These shifting clinical manifestations of HAND are accompanied by changes in pathologic observations which have transitioned from a prominent subcortical pathology characterized by neuronal loss, astrogliosis, and microgliosis to more subtle cortical and hippocampal alterations in synaptic number, functional connectivity, and neuroinflammation (Saylor et al., 2016). Despite the change in the neuropathology observed, white matter alterations and dysfunction continue to persist in PLWH on ART (Müller-Oehring et al., 2009; Tate et al., 2010). MRI and DTI studies have demonstrated numerous changes including thinning of the corpus callosum, reduction in blood flow to the white matter, and loss of volume from the superior longitudinal fasciculus, superior corona radiata, and the internal capsule, all major white matter tracts (Gongvatana et al., 2011; Tate et al., 2011; Corrêa et al., 2015). Furthermore, transcriptome analysis of PLWH on ART identified dysregulation of genes associated with oligodendrocyte maturation and myelination, such as myelin-associated glycoprotein (MAG), MOG, MBP, and oligodendrocyte transcription factor 1 (Olig1) (Borjabad et al., 2011; Solomon et al., 2019). Importantly, the decreases in these oligodendrocyte markers are among the twelve gene categories that together make a signature for HAND (Solomon et al., 2019).

Following the initial infection, HIV can rapidly enter the CNS, typically via the trafficking of CD14/CD16+ monocytes and possibly CD4+ T cells; from there, HIV is released where it primarily targets myeloid cells, including microglia and different populations of CNS-resident macrophages. Astrocytes appear to be restrictively infected with HIV, while OPCs and oligodendrocytes are not infected due to their lack of CD4 receptor expression even though CD4-independent entry has been previously described (Jensen et al., 2019; Nickoloff-Bybel et al., 2021). Thus, as in the other diseases discussed previously, the effects of HIV infection are mediated by a “bystander effect”, whereby infected microglia/macrophages and uninfected immune responsive cells release a wide range of damaging molecules, including cytokines, glutamate, reactive oxygen species, and nitric oxide. Our laboratory has demonstrated that exposure of primary rat OPC cultures to supernatants from primary human monocyte-derived macrophages infected with HIV (HIV/MDMs) significantly inhibits oligodendrocyte maturation (Roth et al., 2021a). Mechanistic studies revealed that activation of AMPARs and kainate receptors by glutamate on differentiating OPCs leads to activation of the ISR (Roth et al., 2021a). There is evidence that ISR activation in OPC results in an inhibition of differentiation; however, the data regarding ISR function in the oligodendrocyte lineage is complex as others have demonstrated that it can have beneficial effects, especially in the context of inflammatory demyelination (Chen et al., 2019, 2021). Viral proteins, secreted from infected cells, can also significantly impair oligodendrocyte maturation and myelination, though the prevalence of this in individuals who are virally suppressed is debated. In a transgenic mouse model with astrocyte-driven trans-activator of transcription (Tat) protein, there is disruption of myelin in the caudate-putamen and significantly decreased levels of MBP and MAG in the striatum (Zou et al., 2015, 2019). Similar to what was observed in our studies using HIV/MDMs, blockade of glutamate-induced calcium influx prevented Tat-mediated effects on oligodendrocyte differentiation, morphology, and myelination, suggesting that inflammation and viral proteins potentially converge on this pathway to negatively impact oligodendrocyte health (Zou et al., 2015). HIV Tat protein also downregulates protein expression of the oligodendrocyte-specific transcription factor, myelin regulatory factor (Myrf), an important determinant of oligodendrocyte maturation and myelination, in the striatum of HIV-Tat transgenic mice (Emery et al., 2009; Flounlacker et al., 2023). Surprisingly, despite a reduction in Myrf, there were no changes in MBP expression in the striatum, though this may be explained in part by the long half-life of MBP and the time points analyzed in the study (Shapira et al., 1981; Flounlacker et al., 2023). Additionally, other studies have demonstrated that the effects of Myrf depletion are more evident in OPCs as they often fail to differentiate or engage in remyelination (Steadman et al., 2019; Duncan et al., 2024). Thus, even in the absence of ongoing viral replication in the CNS, HIV can promote a chronic neuroinflammatory environment that contributes to white matter injury in HAND.

The introduction of ART was expected to mitigate the impact of HIV on the CNS; however, the persistence of neurologic symptoms suggests that, in part, the antiretrovirals themselves may be contributing to the white matter pathology observed. Extensive work in our laboratories has demonstrated that direct exposure of OPCs to antiretrovirals from a variety of classes (e.g. integrase strand inhibitors and protease inhibitors) significantly inhibit oligodendrocyte maturation and remyelination capacity following toxin-induced demyelination (Jensen et al., 2015; Festa et al., 2021, 2023; Roth et al., 2021b; Monnerie et al., 2023). The mechanisms mediating these effects broadly fall into three major categories: ER stress, organellar dysfunction, and disruption of lipid synthesis. Phosphorylation of eukaryotic initiation factor 2 alpha (pEIF2α) and nuclear translocation of activating transcription factor 4 (ATF4), hallmarks of ISR activation, are observed in differentiating oligodendrocyte cultures treated with the integrase strand transfer inhibitor, elvitegravir (Roth et al., 2021b; Monnerie et al., 2023). Preventing the activation of the ISR via the pre-treatment with ISR inhibitor, Trans-ISRIB, was able to mitigate elvitegravir-induced inhibition of differentiation (Roth et al., 2021b). Lysosomal stress, including de-acidification, has also been reported in primary rodent OPC cultures treated with either protease inhibitors or an integrase strand transfer inhibitor (Festa et al., 2021, 2023). This de-acidification is sufficient to reduce differentiation and myelin protein expression in vitro; importantly, activation of the non-specific lysosomal cation channel, transient receptor potential mucolipin 1 (TRPML1), is able to restore both lysosomal pH as well as oligodendrocyte maturation (Festa et al., 2021, 2023). Exposure to antiretrovirals can also induce significant changes in lipid metabolism, including altered processing of the major regulators of lipid metabolism, sterol regulatory element-binding proteins 1 and 2 (SREBP1/2), and reduction of lipid enzymes in the fatty acid synthesis pathway; furthermore, these changes in lipids are associated with reduced expression of myelin proteins, such as PLP (Monnerie et al., 2023). The effects of antiretrovirals on the white matter are not limited to direct toxicity on oligodendrocytes; accumulating evidence suggests that antiretroviral-treated microglia, even in the context of viral suppression, exhibit an inflammatory phenotype (Ryan et al., 2020; Schlachetzki et al., 2024). In a tri-culture iPSC model containing neurons, astrocytes, and microglia (iMg), infected iMg treated with an antiretroviral exhibited a distinct inflammatory phenotype characterized by CD40/RhoGDI pathway activation and TNF-α production (Ryan et al., 2020). This increase in cytokine production, albeit in IFN-responsive genes as opposed to TNF-α secretion, is observed in HIV RNA+ microglia from virally suppressed post-mortem tissue samples (Schlachetzki et al., 2024). Surprisingly, little is known currently about the impact of HIV-infected T cells directly on the oligodendrocyte lineage, despite their known neurotoxic role in other neurologic diseases. Thus, there is clearly a dynamic interplay between HIV infection and antiretrovirals that impacts the neuroimmune environment and ultimately induces white matter injury.

SARS-CoV2

In contrast to HIV, long-lasting brain infection with SARS-CoV2 is rarely observed in postmortem tissue and/or CSF (Lee et al., 2021; Remsik et al., 2021; Yang et al., 2021). This is not to say that SARS-CoV2 does not exhibit neuroinvasive properties as in vitro tropism has been described for choroid plexus cells, astrocytes, and neurons in organoid models as well as astrocytes in fetal cortical slice cultures (Pellegrini et al., 2020; Song et al., 2021b; Andrews et al., 2022). Additionally, a recent study demonstrated that recombinant SARS-CoV2 spike S1 protein accumulated within the skull-meninges-brain axis in mice; however, it is important to note that spike S1 protein was administered intravenously and it is presently unclear how much this represents respiratory infection (Rong et al., 2024). Thus, it seems unlikely that this virus results in a CNS reservoir that continues to induce damage once the initial infection has resolved. Instead, evidence suggests that respiratory inflammation caused by the initial SARS-CoV2 infection results in systemic release of cytokines and chemokines that can induce CNS inflammation (Monje and Iwasaki, 2022). Studies involving a mouse model of mild SARS-CoV2 infection with no discernable illness and no evidence of viral entry into the CNS have demonstrated persistently elevated cytokines and chemokines in the CSF, along with subcortical and hippocampal WM reactivity lasting for at least seven weeks (Fernández-Castañeda et al., 2022). Single-cell RNA-seq in this mouse model revealed a subpopulation of microglia that shared a transcriptional state with white matter-associated microglia (WAM) and disease-associated microglia (DAM); however, they also exhibited distinct alterations in chemokine expression, including Ccl2 and Cxcl10 (Keren-Shaul et al., 2017; Safaiyan et al., 2021; Fernández-Castañeda et al., 2022). This pattern of subcortical WM-enriched microglial reactivity was also found in human brain samples from individuals who died with or after mild or moderate SARS-CoV2 infection (Fernández-Castañeda et al., 2022). These altered microglial transcriptional states were associated with a reduction in OPC number, loss of subcortical mature oligodendrocytes, and fewer myelinated axons (Fernández-Castañeda et al., 2022). Transcriptomic analysis of post-mortem tissue from acute SARS-CoV2-infected individuals demonstrated that, in the brainstem, there was a significant reduction in OPALIN+ oligodendrocytes, a marker expressed by myelinating oligodendrocytes and induced during differentiation (Golan et al., 2008; Radke et al., 2024).

Autoimmunity has also emerged as a potential mechanism mediating SARS-CoV2 oligodendrocyte injury. In individuals with neurologic symptoms during infection, activated T cells and expansion of unique T cell clones were found in the CSF but not the blood, suggesting a compartmentalized response to a CNS antigen; additionally, enrichment of B cells was also found in the CSF of Covid-19 patients compared to controls (Song et al., 2021a). In rare instances, infection with SARS-CoV2 can trigger myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and immunological cross-reactivity between MOG and nucleocapsid viral protein has been reported (Schanda et al., 2024). However, it is presently unclear how common autoantibodies are in mild to moderate SARS-CoV2 infection and how they contribute to persistent neuroinflammation and cognitive dysfunction.

Conclusions

In each of the neurologic conditions discussed above, it is apparent that deleterious alterations in the CNS, including activation of astrocytes and microglia, infiltration of peripheral immune cells, autoimmunity, and disruption of homeostasis, promote prolonged neuroinflammation and converge on the oligodendrocyte lineage to induce blockade of myelin formation, loss of mature myelin, and/or suppression of remyelination. This results in poor clinical outcomes and persistent functional deficits in these patients. The question that arises is whether there is the potential to replace the myelin once it has been lost and if this will restore function. Disease-modifying therapeutics targeted to autoimmune, inflammatory attacks in relapse-remitting MS have successfully reduced the likelihood of developing new white matter lesions, clinical relapses, and stepwise accumulation of disability (Reich et al., 2018). The time between inflammatory relapses allows for endogenous remyelination to occur and typically lead to partial neurologic recovery, thus demonstrating the utility of immune-mediated therapies in the context of autoimmune-induced myelination. However, as the disease progresses, this remyelination process fails and clinical disability worsens. The reasons why this occurs is currently being investigated but it seems that compartmentalized CNS neuroinflammation, seen in both MS and the neurologic disorders described here, is a major barrier to myelin repair. Thus, a two-pronged approach of targeting OPCs to promote remyelination as well as resolving CNS neuroinflammation will likely be necessary for clinically relevant outcomes.

Over the past several years, preclinical animal models have demonstrated the efficacy of targeting CNS neuroinflammation to ameliorate WM injury across neurologic diseases. For instance, in several murine models of perinatal WMI, targeting of different pathways has been tested, including serotonin (5-HT) receptors, oxytocin receptors, galectin-3 administration, and microRNA processing (Mairesse et al., 2019; Bokobza et al., 2022, 2023; Wang et al., 2022b). All of these approaches modulated either astroglial or microglial reactivity which in turn rescued hypomyelination, long-term functional connectivity, and in some instances, behavior. Similar strategies have been applied to TBI and to lesser extent following viral infections. Thus far, none of these promising animal studies has resulted in an approved therapy for any of these conditions. There are several potential reasons for this disconnect between preclinical animal models and the clinic. The first is that a strategy that works under one specific controlled condition, such as the fluid percussion model of TBI, may not necessarily translate to other preclinical models (e.g. closed head impact with rotation) and thus will fail to have broadly translatable effects. Another is whether the animal models used accurately represent the complex neuroimmune and neuropathology observed in humans in terms of both temporal progression and cellular processes. The development of human induced pluripotent stem cell (iPSC)-derived oligodendrocytes and myelinating organoid models should provide important insight as to whether the mechanisms observed in rodent models are conserved in human cells (Douvaras and Fossati, 2015; Kerman et al., 2015; Ehrlich et al., 2017; Madhavan et al., 2018). These comparative studies are being conducted with important differences noted between rodent and human cells, including the ability of astrocytes to promote neuronal maturation, the response of astrocytes to inflammatory stimuli, and species-dependent diversity of the myelin proteome and oligodendrocyte transcriptome (Gargareta et al., 2022; Smith et al., 2022; Lendemeijer et al., 2024). Additionally, proof-of-concept studies have successfully demonstrated that transplantation of CRISPR-edited human OPCs could improve remyelination outcomes in rodents (Wagstaff et al., 2024). Lastly, the therapies tested typically only target the neuroinflammatory environment or OPC differentiation rather than both. The biggest roadblock to myelin repair across this spectrum of disorders is the presence of persistent neuroinflammation that maintains an inhibitory microenvironment which suppresses endogenous OPC differentiation and myelination mechanisms. Removing this barrier will improve myelin integrity and restore neuronal function.

WMI is a common feature of numerous neurologic disorders and in most diseases has been thought of as a consequence of neuronal injury rather than an initiating step. Recent evidence indicates that OPCs and oligodendrocytes play an active role in clinical outcomes and potentially in promoting neuroinflammation. Future work should continue to focus on elucidating the mechanisms of oligodendrocyte injury, the persistence of compartmentalized CNS inflammation, and the translational relevance of current preclinical models to identify novel therapeutic targets.

Main Points.

• Oligodendroglial injury is seen across neurologic diseases.

• Compartmentalized CNS neuroinflammation impairs OPC differentiation and remyelination

• Infiltration of the peripheral immune system contributes to the development of neuroinflammation