Regulation of CNS precursor function by neuronal chemokines

Journal Pre-proof Regulation of CNS precursor function by neuronal chemokines Adrianne Eve Scovil Watson, Kara Goodkey, Tim Footz, Anastassia Voronova

PII:

S0304-3940(19)30636-6

DOI:

https://doi.org/10.1016/j.neulet.2019.134533

Reference:

NSL 134533

To appear in:

Neuroscience Letters

Received Date:

21 June 2019

Revised Date:

16 September 2019

Accepted Date:

1 October 2019

Please cite this article as: Scovil Watson AE, Goodkey K, Footz T, Voronova A, Regulation of CNS precursor function by neuronal chemokines, Neuroscience Letters (2019), doi: https://doi.org/10.1016/j.neulet.2019.134533

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Title: Regulation of CNS precursor function by neuronal chemokines Authors: Adrianne Eve Scovil Watson1, Kara Goodkey1, Tim Footz1 and Anastassia Voronova1-4 # Affiliations: Department of Medical Genetics1, Neurosciences and Mental Health Institute2, MS Centre3, Women and Children’s Hospital Research Institute4, Faculty of

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Medicine & Dentistry, University of Alberta, Edmonton, Canada

# Corresponding author ([email protected], Department of Medical Genetics,

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University of Alberta, 8-39 Medical Sciences Building, Edmonton, AB T6G2H7 Canada)

Highlights

Neurons communicate with OPCs via paracrine signalling and/or neuronal

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activity/synapses;

OPCs and NPCs express chemokine receptors and respond to chemokines;

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Neuronally secreted chemokines regulate NPC and OPC migration, survival,

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proliferation and differentiation;

Mutations in chemokine signalling genes are detected both in patients with MS

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and neurodevelopmental disorders, raising the possibility that aberrant neuronprecursor chemokine signalling may play a role in these disorders.

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Abstract

Oligodendrocyte and neural precursor cells (OPCs and NPCs, respectively) in the central

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nervous system (CNS) have diverse roles in development and homeostasis. During development, precursors build the CNS. In adulthood, they maintain their ability to proliferate and generate differentiated progeny, indicating their tremendous potential to regenerate and repair injured or degenerated CNS. How can we utilize this capability? Cross-talk between neurons and OPCs may hold some clues. Neurons communicate with OPCs via two mechanisms: 1) paracrine secretion of ligands, and 2) neuronal activity and bona fide synapses with OPCs. Intriguingly, OPCs express receptors for chemokines,

which are small signalling molecules produced by various cells, including neurons. In addition to inducing chemotaxis, chemokines also regulate cell proliferation, survival and differentiation. In this review, we will summarize the roles of neuronally secreted chemokines and their documented ability to directly regulate the diverse functions of OPCs and NPCs in the developing as well as adult normal and injured CNS. We will focus on the following neuronal chemokines: CCL2, CCL3, CCL20, CCL21, CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12 and CX3CL1. We will discuss the implications for neuronal chemokine signalling in OPCs and NPCs not only in

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developmental myelination and adult CNS regeneration, but also in cognition, behavior,

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neuroinflammation and neuronal function.

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Abbreviations APC - adenomatous polyposis coli ASD – autism spectrum disorder BBB – blood-brain barrier BDNF - brain derived neurotrophic factor CNS - central nervous system cOPC - committed OPC

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CPM - counts per million E – embryonic day EAE - experimental autoimmune encephalomyelitis

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EDSS - expanded disability status scale FKN – fractalkine (CX3CL1)

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FKPM - fragments per kilobase million Gro-1 - growth stimulating activity, alpha (CXCL1)

IFN- - interferon gamma IL-1 - interleukin-1 beta

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IL-8 - interleukin-8 (CXCL8)

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GW – gestational week

ImOLGs – immune oligodendrocyte lineage cells IP-10 - IFN-γ-induced protein 10 (CXCL10) IP-9 - IFN-γ-induced protein 9 (CXCL11)

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LARC - liver activation regulated chemokine (CCL20) MBP – myelin basic protein

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MCP-1 - monocyte chemoattractant protein-1 (CCL2) MIG – monokine induced by IFN-γ (CXCL9) MIP-1α - macrophage inflammatory protein-1α (CCL3) MS – multiple sclerosis NF-κB - nuclear factor-kappa B NG2 - neural/glial antigen 2 NPC – neural precursor cell

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OPC – oligodendrocyte precursor cell OL - oligodendrocyte P – postnatal day PDGF - platelet derived growth factor PDGFR - platelet derived growth factor alpha RFP – red fluorescent protein RRMS - relapse-remitting MS

SLC - secondary lymphoid-tissue chemokine (CCL21) SNP - single nucleotide polymorphism

TGF-β - transforming growth factor beta TNF- - tumor necrosis factor alpha VSMC - vascular smooth muscle cells

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Keywords

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SVZ – subventricular zone

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SPMS - secondary progressive MS

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SDF-1 - stromal cell–derived factor (CXCL12)

Chemokine, neuron-glia interactions, OPC, neural stem cell, oligodendrocyte,

1. Introduction

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neuroinflammation, multiple sclerosis, neurodevelopment

Chemokines (chemotactic cytokines) are secreted signalling molecules that initiate chemotaxis in nearby responsive cells. Chemokines comprise a family of small 8-10 kDa

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proteins that have Cys (cysteine) residues separated by 0-3 amino acids. The distance between Cys residues forms the basis of their nomenclature, ranging from CC, CXC and

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XC to CX3C, where X represents amino acid(s) positioned between the Cys residues in their N-terminus. The CC group of chemokines is the largest, being comprised of 27 members, followed by the CXC group with 17 members, the XC group with 2 members and the CX3C group with just 1 member [1]. Secretion of chemokines is regulated at the level of transcription and translation as well as post-translationally in the endoplasmic reticulum, Golgi, and at or near the cell surface [2]. Chemokine release is also regulated by inflammatory or injurious stimuli [2-5]. In this light, chemokines are translated with a

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~23 amino acid signal sequence, which is usually cleaved prior to secretion of the mature protein [4]. Moreover, chemokines can be truncated from the C- or N-terminus via proteases leading to change in their function (reviewed in [4] and described below in each chemokine section where appropriate). Transport of chemokines inside cells occurs via the canonical protein trafficking pathway associated with endoplasmic reticulum and Golgi [6]. Overall, the secretion of chemokines varies vastly between cell types and activation stimuli and can involve a myriad of secretory pathways, including secretory granules and vesicles [2, 5, 6].

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Chemokines converge their function on ~20 chemokine receptors discovered to

date [7]. Chemokine receptors are G protein-coupled seven transmembrane receptors that were initially discovered in leukocytes and subsequently shown to be critical regulators

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of their recruitment to sites of inflammation [7]. Since their initial discovery in the

immune system, chemokines have been demonstrated to be important in the central

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nervous system (CNS) for microglia, neurons, glia and neural stem cells as well as infiltrating immune cells during neuroinflammation [7-10]. In addition, the role of

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chemokines extends beyond chemotaxis. Chemokines are important in cellular communication, proliferation, survival and differentiation of various CNS cell types [7, 11, 12]. With regards to cellular communication, chemokines and chemokine receptors

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can be expressed by a variety of CNS cells, such as microglia, endothelial cells, astrocytes, oligodendrocytes and neurons [7, 9, 12-18]. This has been recently reinforced with bulk and single-cell RNA sequencing reports from various CNS cell types (e.g. [1924]). Notably, chemokines can have protective or degenerative effects on CNS cells [7,

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12, 13]. This review will focus on the neuronal chemokine regulation of oligodendrocyte

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precursor cell (OPC) function in the developing and adult CNS.

2. Neuron-OPC interactions Oligodendrocytes (OLs) are responsible for the formation of myelin that wraps

around neuronal axons. Moreover, OLs were recently found to regulate presynaptic properties and neurotransmission [25, 26], which suggests OLs have versatile roles in neuron homeostasis and neurotransmission beyond myelin formation and maintenance. The role of OL lineage cells in neuronally driven processes, such as cognition, has been

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recently exemplified through an elegant study, where conditional deletion of BDNF (brain derived neurotrophic factor) receptor TrkB in OPCs led to poor outcomes in cognitive tests [27]. The ability of OLs and myelin to alter neuronal function is further reinforced by a recent study, in which clemastine, an antihistamine drug that showed remyelinating capacity in MS patients [28], reversed neuronal and behavioural deficits in a mouse model of neurodevelopmental Williams syndrome [29]. Furthermore, clemastine rescues behavioral deficits in socially isolated mice [30]. In turn, neuronal activity is known to boost myelination [31-34]. It has been proposed that this activity dependent

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myelination could explain, at least in part, why pianists and jugglers have increased

myelination in specific brain areas [35, 36], while schizophrenia patients, who have

abnormal function of parvalbumin-positive interneurons, have decreased myelination

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[37]. Finally, new OL genesis and myelination influenced by neuronal activity are

necessary for new motor skill learning [32]. Thus, neuron-oligodendroglia interactions

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are important in both developing and adult CNS.

OLs in the developing CNS are generated via a two-step process: 1) neural

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precursor cell (NPC) commitment to OPC formation; and 2) OPC differentiation into OL [38]. In the adult CNS, there are two sources of cells that generate OLs: subventricular zone (SVZ) NPCs and parenchymal OPCs, both of which arise from embryonic NPCs

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and OPCs [23, 39-44]. Neuron-OPC cell-to-cell communication occurs both in the developing and adult CNS in at least two ways [45]: 1) paracrine regulation of OPC function by neuronally secreted ligands [46-48]; and 2) via neuronal activity and bona fide synapses with OPCs [32, 33, 49-52].

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Intriguingly, OPCs and OLs enhance the expression of immune genes, including

chemokine receptors and ligands, in demyelinating conditions in both rodents and

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humans. This raises the possibility that OL lineage cells may have additional roles in modulating immune responses [21, 22, 53]. Similar to immune cells, OPCs are highly migratory and can respond to several chemokines, as discussed below. The roles of chemokine receptors in OPCs, however, extend beyond chemotaxis and include regulation of OPC proliferation, survival and differentiation (Fig. 1 and discussed below). Both inhibitory and excitatory neurons secrete various chemokines in the developing [46, 54] as well as adult healthy and injured CNS [3].

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Chemokines such as CCL2, CCL3, CXCL1, CXCL10, CXCL12 and CX3CL1 affect synaptic responses, neuronal activity and/or neuronal ion channel function [55-60]. Moreover, some reports suggest neuronal activity can in turn trigger chemokine release. For example, CXCL12 is localized in both types of neuronally secreted vesicles, small and dense core vesicles. Additionally, potassium-induced depolarization of neurons leads to a large release of CXCL12 into the culture medium [61, 62]. Similarly, CCL2 is packaged into dense core vesicles and their release is induced by calcium-dependent depolarization from dorsal root ganglion neurons [63]. In contrast, while CCL21 is

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present in the synaptic cleft, pre-synaptic structures and dense core vesicles [64, 65], its release is currently only known to depend on glutamate-induced neuron damage [64]. Pharmacogenetic or optogenetic stimulation of neuronal activity is known to

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increase proliferation and differentiation of OPCs, leading to increased axonal

myelination in murine CNS in vivo [32, 34]. Interestingly, blocking neuronal activity

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dependent vesicle release in cultured neurons or the developing zebrafish nervous system reduces axonal myelination [66-68]. Whether the dependence of neuronal activity-

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induced myelination on vesicular release is linked to chemokine secretion remains to be addressed.

In this review, we will discuss the roles of the known repertoire of neuronal

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chemokines, which has been reviewed elsewhere [3], on OPC function in the developing as well as adult healthy and injured CNS. We will first focus on neuronal chemokines that have more extensive literature on their roles in OPC function (CXCL1, CXCL12 and CX3CL1) and then summarize the roles of the less described neuronal chemokine

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signalling axis in OPCs and NPCs (CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL3,

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CCL20 and CCL21).

3. CXCL1

CXCL1 (C-X-C motif ligand 1) or Gro-1α (Growth Stimulating Activity, Alpha)

plays an important role in mediating OPC and NPC migration and proliferation in the developing central nervous system [69, 70] (Figs. 1-2). In the murine brain, CXCL1 is expressed in neurons, astrocytes, and endothelial cells (Fig. 3A) and is increased after induced seizures in rats [71]. Human studies demonstrate CXCL1 is expressed in neurons

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during gestation (27 to 36 GW) and disappears by 2 years of age [72], which suggests that CXCL1 is functional during CNS development. In agreement, murine neural/glial antigen 2 (NG2)-positive OPCs in the spinal cord white matter tracts express CXCR2, a cognate receptor for CXCL1 (Fig. 3D), and respond to CXCL1 signalling as early as embryonic day (E) 14 [69, 70]. A recent RNA-sequencing report confirms CXCR2 expression in developmental OPCs and demonstrates its highest expression in embryonic spinal cord OPCs (Fig. 4A). At this developmental stage OPCs are regulated by a number of growth factors,

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one of which being platelet derived growth factor (PDGF) [69]. Through CXCR2,

CXCL1 acts synergistically with PDGF to increase OPC proliferation and reduce their migration in the white matter tracts of the developing spinal cord [69, 70]. While the

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mechanism is largely unknown, CXCL1-dependent migration of OPCs may be due to

CXCL1-mediated increase in cell-substrate adhesion [70], but is independent of calcium

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signalling and activation of the cell cycle [73]. In contrast, CXCL1 acts as a chemoattractant for rat SVZ NPCs and increases their migration in culture [74].

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Interestingly, dysmyelinating jimpy mutant mice that harbour a point mutation in proteolipid protein (PLP) show elevated CXCL1 expression that is correlated with elevated OPC proliferation [75]. Moreover, estrogen receptor  (ER) is believed to

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promote axon myelination at least in part by inducing CXCL1 expression [76]. Human fetal OPCs also express CXCR2 and proliferate in response to CXCL1 [77, 78]. Rat ventral midbrain NPCs exhibit increased proliferation in response to CXCL1 [79]. Mouse SVZ NPCs increase differentiation into O4-positive OLs in the

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presence of CXCL1 [80]. In agreement, cultured postnatal CXCR2 knockout murine OPCs have reduced ability to differentiate into O1-positive OLs [81]. In vivo, CXCR2

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knockout leads to decreased OPC proliferation and increased migration, resulting in myelin mis-localization, decreased myelin thickness and hypomyelination leading to impaired nerve conduction velocity [70, 81]. In adulthood, CXCL1 is expressed in astrocytes in white matter surrounding active multiple sclerosis (MS) lesions, but not in astrocytes from normal samples [77]. In vitro, CXCL1 expression in human fetal astrocytes is induced with IL-1 (Interleukin-1 beta), but not with TGF- (Transforming growth factor beta) or IFN- (Interferon

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gamma) [77], suggesting that the inflammatory environment may mediate astrocytic expression and secretion of CXCL1. In an adult murine EAE (Experimental autoimmune encephalomyelitis) model of MS, constitutive overexpression of CXCL1 in astrocytes produced conflicting results. Omari et al. show that CXCL1 overexpression in astrocytes results in less inflammation and demyelination followed by a greater proliferation of OL lineage cells and more remyelination compared to wild type[82]. This protective effect of CXCL1 is supported by a different report showing CXCL1 reduces virally induced OL apoptosis in the spinal cord, while blocking receptor function increases the severity of the

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viral infection [83]. In contrast, Grist et al. show expression of CXCL1 in astrocytes leads to increased severity of EAE that is associated with increased recruitment of neutrophils [84]. This is corroborated by another report, where injections of CXCR2-specific

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antibodies or CXCR2 antagonist were shown to enhance remyelination in lysolethicin-

induced spinal cord demyelination mouse model [85]. These differences in results may

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arise from different constructs used to overexpress CXCL1 that have a direct impact on protein stability [84] suggesting that the concentration and/or duration of CXCL1 may be

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an important determinant in its ability to influence de- and remyelination. Single-nuclei RNA sequencing from MS patient brain lesions show CXCL1 is expressed in pericytes, endothelial cells, vascular smooth muscle cells (VSMCs) and macrophages (Fig. 3C)

addressed.

4. CXCL12

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[22]. The contribution of CXCL1 from these cells to OPC function remains to be

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CXCL12 (C-X-C motif chemokine 12), also known as stromal cell–derived factor

1 (SDF-1), is important for regulation of OPC survival, migration, proliferation and

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differentiation (Fig. 1). Reporter mice expressing CXCL12-RFP (red fluorescent protein) fusion protein demonstrate that CXCL12 is first expressed in E12.5 spinal cord endothelial cells in meninges [86, 87]. Over the course of postnatal development, CXCL12 begins to be expressed in microglia, astrocytes and neurons; expression in these cell types persists throughout adulthood [88, 89]. RNA-sequencing data from murine adult CNS cell types confirms these findings (Fig. 3A) [19]. Interestingly, the expression of meningeal CXCL12 decreases in adulthood [88]. In adult rodent CNS, neuronal

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CXCL12 expression is detected in multiple brain structures, including the cerebral cortex, basal ganglia, amygdala, hippocampus and thalamus amongst others [89]. Widespread neuronal expression of CXCL12 is upregulated in response to spinal nerve ligation, a model for murine neuropathic pain [90]. Similarly, CXCL12 can be detected in active and inactive lesions in MS patients, although the expression appears to be restricted to astrocytes and blood vessels [91]. Furthermore, the level of CXCL12 expression in MS patients is correlated with the degree of disease severity [92]. Brain damage is also associated with a cleaved form of CXCL12, CXCL12(5-67), produced by partial cleavage

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of the N-terminus by the soluble factors matrix metalloproteinase 2 and 9 [93]. Since CXCL12 requires the first 8 amino acids in the N-terminus to bind to its canonical receptor CXCR4 (C-X-C chemokine receptor type 4) [94], partial cleavage in

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CXCL12(5-67) leads to impairment in CXCR4 affinity, inhibition of NPC migration and

induction of apoptosis via signalling through CXCR3 (C-X-C chemokine receptor type 3)

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[95]. The function of CXCR4 is described below and the function of CXCR3 is discussed in the “IFN-γ-inducible chemokines CXCL9, CXCL10 and CXCL11” section.

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CXCL12 mRNA is spliced into various isoforms, such as alpha and beta isoforms [96]. While CXCL12β is exclusively expressed by endothelial cells, the CXCL12α isoform is predominantly expressed by neurons in the adult mouse brain [96]. Exogenous application of CXCL12α to primary mixed OL lineage cell cultures increases

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proliferation of PDGFRα-positive OPCs, as well as increases myelin basic protein (MBP)-positive OLs and myelin segment formation [97]. The major role of CXCL12 in regulating the immune system is believed to be through stimulating the migration and

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adhesion of leukocytes [96]. However, in injured CNS, such as ischemia mouse models, CXCL12 is involved in neurogenesis and angiogenesis (reviewed in [87]).

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OPCs express two receptors for CXCL12: CXCR4 and CXCR7 (C-X-C

chemokine receptor type 7) [98-101]. During development, they are thought to have independent functions, as they have little spatial or temporal overlap of expression in OPCs [98, 99, 102, 103]. CXCR4 is highly expressed in murine OPCs during early embryonic and postnatal development (Fig. 4A) [98]. Interestingly, while CXCR4 expression is decreased during OPC differentiation, the expression of CXCR7 is upregulated during OPC differentiation and peaks in mature OLs [99, 100]. In agreement,

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CXCL12 enhances OPC migration via the CXCR4 signalling axis [98] resulting in activation of the MEK/ERK and PI3K/AKT pathways [104], and inhibition of the MAPK pathway [100]. CXCL12 enhances OPC differentiation via CXCR7 signalling resulting in activation of the ERK1/2 pathway axis [99]. CXCL12 stimulation of fetal human OPCs leads to an increased differentiation into OLs, which display more mature morphology [105]. CXCL12 also enhances NPC migration and survival [98, 106, 107], decreases human fetal NPC proliferation in vitro and in adult human hippocampal slice ex vivo cultures [108], as well as promotes OPC

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survival and proliferation [97, 100]. NPCs isolated from CXCR4 knockout mice have

decreased migration, but not differentiation into OLs [98, 106]. Furthermore, CXCR4

inhibition with function blocking antibodies or siRNA knockdown of CXCR4 in OPCs

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blocks CXCL12-induced proliferation and migration [97, 100]. Specifically, CXCR4

antagonism inhibits the proliferation effect of the neuronal isoform CXCL12α [97]. On

effect on proliferation/migration [100].

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the other hand, CXCR7 knockdown decreases MBP protein expression, but has no direct

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Notably, CXCR4 protein levels are regulated by CXCR7 and Wnt signalling [109, 110]. siRNA knockdown of CXCR7 in OPCs in vitro leads to increased protein expression of CXCL12 and CXCR4 [100]. High activity of Wnt in mice lacking

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expression of Wnt repressor adenomatous polyposis coli (APC) in OL lineage cells increases expression of CXCR4 in corpus callosum and decreases OPC differentiation, resulting in hypomyelination [110]. These mice also display aberrant OPC clustering around blood vessels, which can be rescued with CXCR4/CXCL12 inhibitor AMD3100

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[110]. Moreover, conditional knockout of APC in OPCs leads to displacement of astrocyte end feet from blood vessels and a leaky blood-brain-barrier (BBB) [111]. Thus,

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it is possible that as Wnt signalling decreases during normal development, OPC-specific expression of CXCR4 is downregulated, migration and proliferation decrease and differentiation occurs [110]. While the regulation of CXCR7 expression in OPCs is currently not known, it has been shown to require NF-κB (nuclear factor-kappa B) in rhabdomyosarcoma [112] and its expression is repressed by HIC1 (hypermethylated in cancer 1) in U2OS human osteosarcoma cells [113]. Notably, CXCR4 and CXCR7 were also proposed to form heterodimers to regulate CXCL12-mediated G protein signalling

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([114] and reviewed in [87]), however, the role of these heterodimers in OPCs remains to be addressed. Please note that CXCL12-CXCR4-CXCR7 signalling axis in glioblastoma and ischemia has been extensively reviewed in [87, 115] and will not be discussed here. In contrast to the developing CNS, in which CXCR4 expression is downregulated over time, CXCR4 expression in demyelinated CNS is upregulated [116]. The EAE model shows that the level of CXCR4/CXCL12 expression in spinal cord is tightly linked to the induction of disease, but the levels remain high even after spontaneous recovery, underlining the importance of CXCL12 in the process of myelination [116]. Furthermore,

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CXCL12-positive microglia and astrocytes are present in the corpus callosum of

cuprizone-demyelinated, but not in control mice, and decrease in remyelinating mice, but do not completely disappear [117]. Robust upregulation of CXCL12 in demyelinated

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corpus callosum is accompanied by a sharp increase in CXCR4-, NG2-positive activated OPCs [117]. Additionally, viral-induced demyelination in mice increases both CXLC12

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expression and the number of PDGFRα-, CXCR4-positive OPCs in the spinal cord [118]. Treatment of cuprizone-demyelinated mice with AMD3100, an inhibitor of CXCL12

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binding to CXCR4, or siRNA against CXCR4 prevents OPC differentiation and remyelination, likely due to the inhibition of the migratory action of CXCL12/CXCR4 axis [117]. Additionally, CXCR4 inhibitor AMD3100 causes an increase in OPC

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proliferation in the SVZ, but not within the remyelinating corpus callosum area [117]. In contrast, short term treatment of a viral-induced demyelinated mice with AMD3100 followed by a 2 week recovery period increases the amount of mature OLs and remyelination, and improves clinical scores [118]. The apparent difference in effect of

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AMD3100 could be attributed to different demyelination mouse models or the area of CNS analyzed (brain vs. spinal cord).

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Treatment of cuprizone-demyelinated mice with the CXCR7 antagonist CCX771

increases OPC proliferation and differentiation resulting in enhanced remyelination [119]. Additionally, CXCR7 antagonism has been shown to reduce T-cell infiltration and decrease axonal injury in the spinal cord of EAE mice [120]. While the results obtained in demyelination mouse models with CXCR7 antagonists seem to be contrary to the positive role of CXCR7 in developmental OL formation from OPCs, recent reports suggest that CXCR7 acts as a scavenger receptor internalizing CXCL12 [98, 121, 122],

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which suggests CXCR7 may be limiting the amount of freely available CXCL12. Indeed, demyelinated mice treated with CXCR7 antagonist show increased CXCL12 levels and a slightly elevated number of OPCs positive for phosphorylated CXCR4 [119]. This suggests that inactivation of CXCR7 leads to activation of CXCR4 in OPCs [119]. This is supported by the report that shows CXCR7 knockdown in cultured OPCs increases CXCR4 expression [100]. Finally, when CXCR4 and CXCR7 antagonists are co-applied during remyelination, this leads to decreased OL numbers and myelin intensity in the corpus callosum compared to treatment with CXCR7 antagonist alone, suggesting that

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CXCR7 restricts CXCR4-mediated OPC maturation [119]. Notably, CXCR4 is expressed in immune oligodendroglia (ImOLGs), in addition to immune cells, in brain lesions in MS patients (Fig. 4C) [22]. In the future it will be interesting to understand the role of

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CXCL12-CXCR4 signalling in this novel class of OL lineage cells in neuroinflammation

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and remyelination.

5. CX3CL1

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The only member of the CX3C family, CX3CL1 (C-X3-C motif ligand 1) or fractalkine (FKN), has a unique transmembrane structure which can be cleaved to produce a soluble glycoprotein by metalloproteinases ADAM 10 and ADAM 17 or

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lysosomal cysteine protease and cathepsin S (CatS) [123]. While the cleaved form contains only the chemokine domain located in the N-terminus, the transmembrane form contains the chemokine domain, a mucin-like stalk, a transmembrane domain and an intracellular C-terminal domain [123]. Both the membrane bound and secreted forms of

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CX3CL1 are bioactive. The transmembrane form of CX3CL1 has been proposed to act as an adhesion molecule, and the soluble form to act as a chemoattractant [124]. Notably,

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transmembrane and soluble CX3CL1 elicit different cytokine response from immune cells [125, 126]. Moreover, the CX3CL1-CX3CR1 signalling axis has been shown to have both deleterious and protective effects towards neurons in mouse models of neurological disorders [123]. In this light, neuron-specific expression of soluble CX3CL1, and not the transmembrane form lacking the ADAM10/17 cleavage site, rescues neuronal cell death in a synucleinopathy mouse model [127]. This is corroborated by additional reports showing that infusion of the soluble form of CX3CL1 into the CNS

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has neuroprotective properties in a stroke mouse model [128]. Notably, in addition to widely-studied neuronal death in stroke and alpha-synucleinopathies, there is also extensive, but less studied oligodendroglial cell death and/or myelin deficiency [129132]. It is not currently known whether CX3CL1 has a protective effect on oligodendroglial lineage cells in these conditions. In the developing mouse brain, CX3CL1 is expressed by ventral forebrain inhibitory interneurons that migrate into the developing dorsal forebrain (cortex) and is secreted by interneurons in culture [46]. Ablation of these interneurons in vivo reduces

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the formation of OPCs and decreases CX3CL1-positive cells in the late embryonic

cortical SVZ area, where dorsal OPCs are first generated [46]. Apart from interneurons, CX3CL1 is also expressed in excitatory neurons in the developing mouse cortex [54,

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133] and is regulated by the CXCL12 signalling pathway [133]. In the adult brain,

CX3CL1 is expressed in the hippocampus, olfactory blub, cerebral cortex, amygdala,

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globus pallidus and thalamus [134]. In adult healthy cerebral cortex and in brain lesions in MS patients, CX3CL1 is expressed at the highest level in neurons and at lower levels

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in OL lineage and endothelial cells (Fig. 3A, C) [19, 22]. In healthy adult spinal cord, CX3CL1 expression is restricted to neurons [135]. Interestingly, astrocytes have little to no CX3CL1 expression in a normal CNS (Fig. 3A) [19], but show strong expression in

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response to inflammatory stimuli, such as TNF- (tumor necrosis factor alpha) stimulation or EAE disease [134, 136, 137]. This is corroborated by moderate expression level of CX3CL1 in human astrocytes in MS patient brain lesions (Fig. 3C) [22]. Finally, CX3CL1 is expressed in the choroid plexus in aging and EAE-induced mice [138, 139].

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CX3CR1 is the only murine receptor for CX3CL1 (Fig. 3D) [10]. While CX3CR1

has previously been believed to be expressed exclusively in microglia [140], recent

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reports suggest CX3CR1 is also expressed in neurons [141], neural precursors [16, 46, 108] and OPCs [46] in vivo and in culture, albeit at a lower level. RNA-sequencing of murine embryonic and postnatal OPCs isolated from brain and spinal cord confirms CX3CR1 expression in developing OPCs and shows the highest expression in postnatal day 7 brain OPCs (Fig. 4A) [23]. This is in agreement with elevated expression of CX3CR1 in postnatal OPCs when compared to embryonic OPCs in the developing cortex [46]. While NPCs are not included in the murine adult CNS cell types RNA-sequencing

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analysis [19], Fig. 4B demonstrates CX3CR1 is expressed at the highest level in microglia and at a lower level in OPCs. Finally, single-nuclei RNA sequencing analysis from MS patient brain lesions also shows CX3CR1 is expressed in committed OPCs (cOPCs), immune oligodendroglia (ImOLGs) and microglia/macrophages (Fig. 4C) [22]. In culture, soluble CX3CL1 acts directly on CX3CR1 expressed in murine NPCs and OPCs and enhances their differentiation into OLs without affecting their proliferation or survival [46]. Moreover, when CX3CR1 is specifically knocked down in embryonic NPCs through in utero electroporation, this leads to decreased production of OPCs and

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OLs, but not astrocytes [46]. Intriguingly, mice constitutively lacking one or two copies of CX3CR1 also show decreased oligodendoglial differentiation in postnatal brain [46],

however, this mouse model does not allow for isolating the role of CX3CR1 signalling in

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different cell types. What is the contribution of neuronal CX3CL1 to developmental

oligodendrogenesis? Voronova et al. show that conditioned media from interneurons

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enhances oligodendrogenesis from NPCs in culture, and that this effect is abolished when CX3CL1 is neutralized with anti-CX3CL1 function blocking antibodies [46].

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Interneuron-mediated increase in oligodendrogenesis is also abrogated when CX3CR1 on NPCs is blocked with anti-CX3CR1 function blocking antibodies [46]. In vivo, ablation of interneurons leads to reduced expression of CX3CL1 in the developing cortex and

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reduced OPC numbers [46]. Perinatal lethality of these mice did not allow evaluation of the production of mature OLs [46]. Notably, enhanced production of OL lineage cells is detected in human forebrain organoids that develop from both ventrally and dorsally derived precursors [142]. In these fused organoids, there is an extensive migration of

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ventrally derived cells, which leads to increased OL production when compared to organoids derived only from ventral or dorsal precursors [142]. Whether these effects are

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due to CX3CL1 in migrating ventral interneurons in fused organoids remains to be addressed.

Intriguingly, infusion of soluble CX3CL1 into hippocampus of aged rats increases

proliferation and neurogenic differentiation from hippocampal NPCs, whereas acute block of CX3CR1 with anti-CX3CR1 function blocking antibodies decreases NPC proliferation and differentiation [143]. Currently, it is not clear whether this is due to a direct effect of CX3CL1 on hippocampal NPCs or indirect effect through microglia.

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What is known is that human NPCs isolated from second trimester fetal CNS tissue show increased survival in response to CX3CL1 [108]. Moreover, adult mouse SVZ NPCs exhibit higher neurosphere formation in the presence of CX3CL1, which is indicative of their increased activation and proliferation [139]. CX3CR1 constitutive knockout mice challenged with cuprizone demyelination show decreased myelin debris phagocytosis by microglia/macrophages, aberrant myelin morphology as well as reduced numbers of OPCs, which has been attributed to reduced OPC migration and proliferation [144]. It is tempting to speculate that the deficiencies in

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OPC functions in this mouse model may be attributed to the lack of CX3CR1 signalling

in OPCs, which otherwise express CX3CR1 in both healthy and diseased CNS (Fig. 4B, C) [19, 22]. Mice expressing CX3CR1 with a mutation detected in MS patients

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(CX3CR1I249/M280 [145], Table 1) that makes CX3CR1 less responsive to CX3CL1 [146], have more severe EAE, exhibit a decrease in calbindin-positive neurons and MBP

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staining, as well as an increase in CD45-positive cells in the cerebellum [147]. EAE induction in CX3CR1 constitutive knockout mice also leads to more severe EAE disease

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progression and demyelination as well as increased neurological deficits [148]. Interestingly, some of the increased EAE disease severity in CX3CR1 knockout mice has been attributed to bone marrow and natural killer immune cells, which also

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express CX3CR1 and infiltrate CNS during EAE [148, 149]. When wild-type rats are treated with CNS impenetrant CX3CR1 inhibitor AZD8797, which blocks peripheral leukocyte infiltration, this reduces disease severity and neurological impairments [150]. The difference in the effect of enhanced or decreased CX3CR1 signalling in the outcome

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of de- and remyelination can be attributed to i) differences in CX3CR1 signalling in the peripheral immune system vs. the CNS; or ii) acute vs. chronic depletion of CX3CR1

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signalling. In support of the former, injections of soluble CX3CL1 directly into the CNS lead to neuroprotection, increased neurogenesis as well as improved behavior and cognition in various mouse models of neurodegeneration, aging, schizophrenia and stress [128, 143, 151-154]. Moreover, exogenous CX3CL1 protects CNS cells from demyelination-induced cell death in ex vivo cerebellar slice cultures [155]. In support of the latter, Cipriani et al. show that in a stroke mouse model, constitutive CX3CL1 or CX3CR1 knockout reduces ischemic damage [128]. However, injection of CX3CL1

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directly into the lateral ventricle in wild-type, but not in CX3CL1 or CX3CR1 knockout, mice also reduces ischemic damage and increases neuroprotection [128]. Thus, the authors hypothesize that the absence of the CX3CL1-CX3CR1 signalling axis from early embryonic development alters the microenvironment in the brain. They further suggest that acute vs. chronic manipulation of the CX3CL1-CX3CR1 signalling axis may lead to different outcomes [128]. Indeed, when microglia isolated from wild-type or CX3CL1 knockout mice are subjected to conditioned medium from oxygen-glucose deprived

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neuronal cultures, they elicit different phagocytic activity and TNF- release in response to exogenous CX3CL1 [128]. The response of OPCs with chronic vs. acute manipulation of the CX3CL1-CX3CR1 signalling axis during neurodegeneration remains to be addressed.

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While these positive effects of soluble CX3CL1 in injury, neurodegeneration,

stress and schizophrenia mouse models have been attributed to microglia for the most

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part, a recent report shows overexpression of soluble CX3CL1 by cells lining the lateral ventricle leads to enhanced cognition in a mouse model of Alzheimer’s disease without

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affecting microglial function [156]. Thus, it is tempting to speculate that at least some of the positive effects of CX3CL1 on functional outcomes in the aforementioned studies

6. CXCL8

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could be attributed to the direct role of CX3CL1 on NPCs and/or OPCs.

CXCL8 (C-X-C motif chemokine 8) or interleukin-8 (IL-8) is produced by a variety of CNS cells, including microglia, astrocytes, neural precursors, OLs and neurons

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[157-160] (Fig. 3B). While there are very few reports on neuronal expression of CXCL8, it is known that co-culture of neurons differentiated from human embryonal carcinoma

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cell line with epithelial cells stimulated with TNF- and IFN- results in robust increase in neuronal CXCL8 expression [160]. Moreover, incubation of cultured human neurons with amyloid beta (A) peptide or TNF-, but not CCL2, robustly increases secretion of CXCL8 [158]. However, it should be noted that the total amount of secreted CXCL8 by A- or TNF--stimulated neurons is lower when compared to A-stimulated human microglia or astrocytes [158]. Thus, it is possible that CXCL8 production in neurons may be induced by inflammatory conditions.

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CXCL8 functions via two cognate receptors: CXCR1 (C-X-C chemokine motif receptor 1) and CXCR2 (C-X-C chemokine motif receptor 2) (Fig. 3D). CXCR1 is expressed in NG2-positive human precursors, whereas CXCR2 is expressed in mouse PDGFR-positive OPCs in vivo and in vitro (Fig. 4A) [80] and in mouse and human immature O4-positive OLs [70, 157]. The functional significance of CXCR2 signalling in vivo has been discussed in the CXCL1 section. Exogenous CXCL8 induces CXCR1-dependent cell death of human embryonic

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stem cell (hESC)-derived NPCs, but not purified OPCs or OLs [157]. Notably, CXCL8 enhances migration of human NPCs and OPCs via CXCR1 signalling [157]. In rat ventral midbrain- -derived NPC cultures, CXCL8 increases NPC proliferation [79]. Incubation of Oli-Neu cell line cultures (mouse OPC cell line) with CXCL8 increases OPC

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proliferation and MBP expression, which may indicate enhanced OL differentiation [97] (Figs. 1-2). Interestingly, human fetal exposure to CXCL8 is associated with aberrant

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brain structure formation and increased risk of schizophrenia [161]. It is therefore tempting to speculate that aberrant brain formation and function could be in part caused

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by the effect of CXCL8 on NPCs and OPCs that build the developing brain.

7. IFN--inducible chemokines CXCL9, CXCL10 and CXCL11

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The CXCL9 (C-X-C motif chemokine 9), CXCL10 (C-X-C motif chemokine 10), and CXCL11 (C-X-C motif chemokine 11) genes are located in close proximity in the CXCL cluster on chromosome 4q21.1 indicating that these chemokines have evolved together and could explain, at least in part, why they share the same receptor, CXCR3 (C-

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X-C chemokine receptor 3) (reviewed in [162]). CXCL9, also known as Monokine induced by IFN- (MIG), and CXCL11, also known as IFN--induced protein 9 (IP-9), do

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not appear to be expressed in normal adult CNS cells. However, the expression of CXCL9, CXCL10 (IP-10) and CXCL11 rises in so called ‘endangered’ neurons upon CNS infection in vivo [163, 164]. Moreover, they are in general elevated during CNS inflammation [163-165]. A unifying feature of these chemokines, apart from being induced in endangered neurons, is their induction in response to IFN- (reviewed in [162]). IFN- in turn is critical in mediating antiviral and antimicrobial immunity [166] and is significantly elevated during CNS infection and inflammation [167-169]. Hence,

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CXCL9, CXCL10 and CXCL11, together with IFN-, are often referred to as inflammatory chemokines [162, 170]. In EAE, robust upregulation of CXCL9, CXCL10 and CXCL11 expression precedes upregulation of CXCR3 expression [170], and this expression upregulation is maximal during disease peak [165, 170, 171]. The role of CXCL9, CXCL10 and CXCL11 in EAE has not been completely elucidated. In vivo administration of exogenous CXCL11 fused to immunoglobulin protein, which is particularly useful in evaluating T-cell stimulation [172], suppresses

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ongoing EAE and provides a prolonged state of disease resistance [173]. For CXCL10, there is conflicting evidence in the literature. Klein et al. show CXCL10 knockout mice display increased susceptibility to EAE, however, treatment of wild-type mice with

CXCL10-specific antibodies does not affect incidence or severity of the EAE [174]. In

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contrast, Narumi et al. demonstrate neutralization of CXCL10 with function blocking antibodies in rats exacerbates EAE severity [175]. Finally, conditional ablation of

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CXCL10 in astrocytes delays clinical onset of EAE, but does not impact axonal loss [176]. Skripuletz et al. show ablation of astrocytes diminishes, but does not completely

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suppress CXCL10 expression in cuprizone-demyelinated mice [177]. This suggests that other cells, such as damaged or endangered neurons in demyelinated CNS, may express CXCL10. While the precise role of CXCL9, CXCL10 and CXCL11 in de- and

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remyelination remains elusive, it is commonly accepted that CXCL9, CXCL10 and CXCL11 act as chemoattractants for immune cells expressing CXCR3 to infiltrate the CNS, which contributes to the neuroinflammation-associated CNS pathology [162]. CXCR3 knockout mice develop more severe chronic EAE diseases with increased

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demyelination and axonal damage in both spinal cord and cerebellum at least in part due to aberrant distribution and reduction of regulatory T-cells [178]. When CXCR3

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knockout mice are challenged with cuprizone-induced demyelination, however, they do not develop a more severe demyelination, but display less active microglia, astrocytes and reduced expression of inflammatory cytokines, such as CXCL9, CXCL10, CCL2, IFN- and others [179]. While the numbers of OPCs and OLs in cuprizone-demyelinated CXCR3 knockout animals were not measured, remyelination was not different from wildtype mice [179]. CXCR3 antagonists prevent, delay the onset of and/or reduce the severity of EAE disease [180, 181] at least in part due to reduction in immune cell

19

infiltration into the CNS without affecting T-cell ability to respond to MOG immunization or to transfer EAE [181]. With regards to OPCs, which express CXCR3 in the brain (Fig. 4A and [182, 183]), both CXCL10 and IFN-, through induction of CXCL10, induce apoptosis of mouse and human OPCs [182, 183]. In agreement, OPCs isolated from CXCL10 knockout mice have reduced cell death and are less susceptible to apoptosis with IFN- treatment [182]. Likewise, OPCs isolated from CXCR3 knockout mice show decreased

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apoptosis when treated with CXCL10 or IFN- [182]. Interestingly, CXCL1 protects OPCs from CXCL10- or IFN--induced cell death via CXCR2 receptor signalling [183] providing an interesting crosstalk between these different chemokines that could be

important to both understand and potentially treat demyelinating disorders. Moreover,

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astrocyte-secreted CXCL10 inhibits OL differentiation from OPCs [184]. Exogenous

CXCL9 increases OL maturation from adult mouse SVZ NPCs without affecting NPC

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cell survival, proliferation or migration [80]. While the role of CXCL11 is not currently known in NPCs or OPCs, CXCR7, which can bind CXCL11 and CXCL12, has been

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reported to act as a scavenger receptor internalizing both CXCL11 and CXCL12 [121, 122]. Considering CXCL11 is upregulated in inflamed CNS [162, 170], and OPCs were recently reported to express immune genes and internalize myelin debris in EAE mice

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[21], it would be interesting to investigate the role of the CXCL11-CXCR7 axis in OPCs in diseased or injured CNS for their ability to respond to and internalize this

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inflammatory chemokine.

8. CCL2

CCL2 (chemokine ligand 2), also known as MCP-1 (monocyte chemoattractant

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protein-1), is expressed in dorsal root ganglion neurons in various rodent models of neuropathic pain (reviewed in [185]). Furthermore, it has been suggested that CCL2 gets packaged into neuronal vesicles for the delivery into spinal cord [186, 187], where it could potentially signal to microglia expressing the cognate receptor CCR2 (C-C chemokine receptor type 2) (reviewed in [185]). In the brain, CCL2 is expressed in astrocytes and neurons in various structures, such as the cerebral cortex, hippocampus, hypothalamus, substantia nigra and cerebellum amongst others [188]. Notably, in MS

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patient brain lesions, CCL2 is predominantly expressed in astrocytes and endothelial cells (Fig. 3C) [22]. CCR2 is expressed in cultured OPCs [189]; however, exogenous CCL2 does not affect postnatal cortical OPC survival or differentiation [189]. There was a CCL2mediated decrease on OPC proliferation, however it was not statistically significant [189]. RNA-sequencing of purified PDGFR-positive OPCs demonstrates CCR2 is preferentially expressed in spinal cord and not brain postnatal OPCs (Fig. 4A) [23]. This

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could explain why cortical OPCs had minimal to no response to CCL2 [189]. In the future, it would be interesting to analyze the response of CCR2-positive spinal cord OPCs to CCL2. Interestingly, activated cortical OPCs in cuprizone-demyelinated brains express both CCL2 and CCR2 [53]. Moreover, incubation of activated OPCs with CCL2

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increases their migration [53]. Similarly, CCR2 is also important for NPC migration

[190]. CCR2 deficient (knockout) NPCs fail to migrate towards the inflammatory site

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when transplanted onto TNF- and IFN- treated hippocampal slices [190].

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9. CCL3

CCL3 (C-C motif ligand 3), also known as MIP-1 (macrophage inflammatory protein-1), is expressed in cultured cortical neurons of the developing mouse brain [54].

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In the adult human brain, CCL3 is expressed predominantly in neurons in Alzheimer’s disease patients [191]. Interestingly, elevated CCL3 levels are found in mouse models of epilepsy [192, 193], Alzheimer’s disease [194, 195] and MS (EAE) [196], raising the

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possibility that this chemokine is associated with pathological mechanisms of neurodegeneration.

The cognate receptor for CCL3, CCR1 (C-C chemokine receptor type 1, Fig. 3D),

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is expressed in cultured OPCs [197]. RNA-sequencing data from purified OPCs suggest CCR1 and another CCL3 receptor, CCR5 (C-C chemokine receptor type 5, Fig. 3D), are expressed in vivo at the highest level in embryonic spinal cord and postnatal brain OPCs, respectively (Fig. 4A) [23]. Stimulation of purified rat OPCs with CCL3 leads to a decrease in migration of OPCs with no effect on proliferation [197]. In agreement, exogenous CCL3 has no effect on human NPC proliferation [108]. This is in contrast to

21

CCL3-mediated chemoattraction and increased migration of CCR1- and CCR5-positive mononuclear cells from the circulating pool into the CNS [198]. Importantly, CCR1 knockout is protective against EAE disease initiation, at least in part due to reduction in monocyte infiltration [199]. On the other hand, Tran et al. have demonstrated CCL3 or CCR1 knockout mice do not differ in EAE disease initiation or severity [200]. The differences between these studies may lie in the myelin protein peptide used to immunize the animals, which may represent different stages of MS [200]. It is also possible that acute vs. chronic depletion of CCL3 signalling may have different

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effects on EAE. For example, mice with constitutive knockout of CX3CL1 or its cognate receptor CX3CR1 have less severe injury in a mouse model of stroke [128]. Yet, acute infusion of exogenous CX3CL1 is neuroprotective in wild-type mice subjected to the

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same stroke paradigm [128]. In agreement, wild-type rodents treated acutely with CCL3specific antibodies or CCR1 antagonist BX-471 show reduced EAE disease initiation and

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severity, respectively [201, 202]. Finally, CCR5 knockout mice develop less severe EAE with decreased immune cell infiltration and microglia activation [203]. Interestingly,

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NG2- and O4-positive oligodendroglial cells are reduced in CCR5 knockout mice with EAE most probably due to decreased demyelination [203]. The direct role of CCL3 on

10. CCL20

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OPCs in MS mouse models remains to be addressed.

CCL20 (C-C motif ligand 20) is also known as LARC (liver activation regulated chemokine) or MIP3A (macrophage inflammatory protein-3). CCL20 is not expressed in

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healthy adult CNS [204], but is elevated in vivo in hippocampal neurons after traumatic brain injury [205] and in astrocytes in EAE mice [204]. CCL20 acts through CCR6 (C-C

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chemokine receptor 6, Fig. 3D). CCR6 knockout mice display more severe EAE disease progression at least in part due to decrease in splenic dendritic cells [206]. Intriguingly, CCR6 is not required by T-cells to induce EAE as shown by similar EAE disease onset when either wild-type and CCR6 knockout antigen re-stimulated T-cells were transferred to WT or CCR6 knockout mice [206]. RNA-sequencing analysis of purified murine adult CNS cells shows CCR6 is also expressed in microglia/macrophages and to a lower extent in OPCs (Fig. 4B) [19]. Moreover, postnatal spinal cord OPCs express the highest level

22

of CCR6 (Fig. 4A) [23]. While the direct role of the CCL20-CCR6 signalling axis in OPCs is currently not known, exogenous CCL20 is known to increase OL cell death in culture [205]. Furthermore, human NPCs express CCR6 and exhibit higher migration in response to CCL20 [8] raising the possibility that CCL20 may have a direct effect on OPC function as well.

11. CCL21 CCL21 (Chemokine [C-C motif] ligand 20), also known as secondary lymphoid-

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tissue chemokine (SLC), is rapidly expressed and secreted from dissociated cortical

excitatory neurons in culture and hippocampal neurons in ex vivo slices when treated with neurotoxic glutamate [64]. It has also been shown that CCL21 is expressed in cortical

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neurons after ischemia [207]. Its vesicular secretion from neurons occurs via the trans-

Golgi apparatus and is dependent on the presence of an intact N-terminus [65]. Cognate

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receptors for CCL21, CCR7 (C-C motif chemokine receptor 7) and CXCR3 (Fig. 3D), are expressed in developing OPCs in vivo (Fig. 4A) [23] and in human NPCs in vitro [8]. and CXCL11” section.

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The role of CXCR3 was discussed in “IFN-γ-inducible chemokines CXCL9, CXCL10

Similarly to microglia/macrophages [64], human NPCs stimulated with CCL21

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exhibit increased migration [8]. Interestingly, CCL21 promotes neuronal, but not astrocyte or OL differentiation of mouse SVZ NPCs [80]. The role of CCL21-CXCR3 or CCL21-CCR7 in OPCs in the developing and remyelinating CNS remains to be

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addressed.

12. Discussion and conclusions

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While the name “chemokine” implies chemotaxis, it is clear that chemokines play

multiple roles in CNS precursor function, including proliferation, survival, differentiation and migration (Figs. 1-2). Notably, each chemokine can affect multiple cell functions. For example, CXCL1 reduces OPC death and migration, but increases proliferation and differentiation (Fig. 1). Thus, it is not surprising that chemokine receptors have been implicated in OPC and NPC function both in CNS development and regeneration.

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The identification of a novel immune class of OL lineage cells, including OPCs, in neurodegenerative conditions [21, 22] and the dynamic expression of chemokines in so called “endangered” neurons in injured or infected CNS [3] suggest that there may be novel chemokine-mediated mechanisms of neuron-oligodendroglia communication in demyelinating conditions. Moreover, this poses a new question about the role of these immune OL lineage cells in neuroinflammation as well as CNS regeneration and remyelination. Finally, microglia and OPCs share common immune genes, including chemokine receptors, in demyelinating conditions [21, 22, 53]. Miron et al. elegantly

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showed alternate state microglia/macrophages associated with anti-inflammatory

cytokine production (formerly known as M2), secrete paracrine ligands that promote OPC differentiation [208]. In the future, it will be important to address how immune

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ligands, including chemokines, affect microglia-OPC cell-to-cell communication.

Chemokines and their receptors are often mutated in MS patients and have been

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proposed to have protective, detrimental or disease attenuating function (Table 1). Notably, while chemokine ligands display mutations in non-coding regions, such as the

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promoter and 3’-UTR (untranslated region), chemokine receptors mutations are primarily detected in protein coding regions (Table 1). This could indicate that mutations in chemokines can potentially affect their expression or mRNA stability ultimately resulting

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in the availability of the chemokine ligand, while mutations in receptors may primarily affect their function. Indeed, some of the single nucleotide polymorphisms (SNPs) in the CCL2 gene have been associated with increased levels of CCL2 protein expression [209], whereas mutations in CX3CR1 affect its ability to respond to CX3CL1 and/or activate

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downstream Akt signalling [146, 210]. It is tempting to speculate that mutated chemokine receptors in OPCs could contribute to MS onset and/or progression. An interesting

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observation that OPCs express functional chemokine receptors and other immune genes [21, 53], as well as their ability to perform myelin debris phagocytosis [21] and present antigens to cytotoxic T-cells [211], have led Jakel et al. to propose that OL lineage cells could actively participate in the “inside-out” mechanism of neurodegeneration in MS [22]. Chemokine signalling network members are also mutated in neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD) and Schizophrenia (Table 2).

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Mutations in chemokine ligands and receptors and their signalling pathways are enriched in analysis of schizophrenia risk genes [212]. Intriguingly, OPCs have been recently shown to directly contribute to cognition through BDNF-TrkB signalling [27]. Moreover, hippocampal NPCs have long been known to participate in behavioural and cognitive processes through postnatal and adult neurogenesis [213]. Finally, ASD-risk genes and environmental factors are known to play an important role in cortical NPCs, ultimately impacting neural circuitry development [15, 214-217]. Could chemokine signalling in OPCs and/or NPCs contribute to these physiological processes? Moreover, could mutated

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chemokine ligands and receptors in OPCs and/or NPCs contribute to the development of

neurodevelopmental disorders? This is a particularly interesting hypothesis in light of the fact that CX3CR1 constitutive knockout mice have reduced sociability in juveniles and

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adults, as well as increased self-grooming in response to stress in adults. This is

accompanied by reduced functional connectivity in the prefrontal cortex and aberrant

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synapse formation [218]. Moreover, infusion or overexpression of CX3CL1 in the CNS leads to behavioural deficit rescue in the BDNFVal66Met mouse model [153] and cognitive

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improvement in the tauopathy mouse model [156]. It is tempting to speculate that chemokine signalling in CNS precursor cells, such as the CX3CL1-CX3CR1 signalling axis, may play an important role in cognition and/or behaviour. While this question is

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important to address in the field of neurodevelopment, the generated information could also be useful for understanding and treating cognitive decline and depression in patients with MS and other immune disorders [219].

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13. Acknowledgements.

A.W., K.G., T.F. and A.V. co-wrote the manuscript and K.G. created the figures. A.W. is

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supported by the University of Alberta, Faculty of Medicine & Dentistry 75th Anniversary Award, K.G. by University of Alberta Research Initiative summer studentship and A.V. by Canada Research Chair Tier II in Neural Stem Cell Biology. This work was funded by grants to A.V. from CIHR (#161466), MS Society of Canada (#3573) and University of Alberta Hospital Foundation. We thank Dr. Jason Plemel for helpful discussions and Dr. Plemel and Jessica Li for reading the manuscript.

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Figure legends.

Fig. 1. Summary of direct effect of neuronal chemokines [3] on OPC survival, proliferation, differentiation and migration. A positive (enhancing) effect on OPC function is displayed with chemokines and upward arrows in blue. A negative (inhibitory) effect is displayed with chemokines and downward arrows in red. Please note CCL20 has an effect on oligodendrocyte (OLs) cell death. Please see text for details and references.

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This figure was generated using BioRender and Adobe Illustrator.

Fig. 2. Summary of direct effect of neuronal chemokines [3] on NPC survival,

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proliferation, differentiation and migration. A positive (enhancing) effect on NPC function is displayed with chemokines and upward arrows in blue. A negative (inhibitory)

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effect is displayed with chemokines and downward arrows or lines in red. Please note CCL21 increases neurogenic differentiation (marked with an asterisk). Please see text for details and references. This figure was generated using BioRender and Adobe Illustrator.

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Fig. 3. Expression of chemokines in CNS cell types. (A): Expression of CCL2, CCL3,

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CXCL1, CXCL10, CXCL12 and CX3CL1 mRNA was extracted from bulk RNAsequencing analysis of purified cells from murine adult cerebral cortex tissue using the BrainRnaSeq.org database [19]; (B): Expression of CXCL8 mRNA was extracted from

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bulk RNA-sequencing analysis of purified cells from human CNS tissue using the BrainRnaSeq.org database [20]. Error bars are SEM. Please note the logarithimic y-axis scale. FKPM = Fragments Per Kilobase Million; h = human; OPC = oligodendrocyte precursor cell. (C): Expression of CCL2, CXCL1, CXCL8 and CX3CL1 mRNA from

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single-nuclei RNA sequencing analysis of human MS patient brain lesion tissue using the Ki.se/en/mbb/oligointernode database [22]. Data is presented as a heatmap generated in

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Prism8, where purple has the lowest level of expression and red has the highest level of expression. 23 cell types and the expression levels of chemokines are presented across individual rows. Please note that other chemokines discussed in this review were below the detection limit or not expressed. ImOLGs = Immune oligodendroglia; VSMCs = vascular smooth muscle cells; Oligo = Oligodendrocyte cluster; cOPC = committed OPC. (D): Diagram of chemokine ligand – receptor cognate pairs. Chemokine ligands are listed using conventional and official gene symbols. Please see text for details.

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Fig. 4. Expression of chemokine receptors in CNS cell types. (A-B): Expression of CCR1-2, CCR5-7, CXCR2-4, CXCR7 and CX3CR1 mRNA was extracted from bulk RNA-sequencing analysis of purified PDGFR-positive OPCs in murine embryonic and postnatal brain and spinal cord tissue [23] (A) or purified cell types from murine adult cerebral cortex tissue [19] (B) using the Ki.se/en/mbb/oligointernode or BrainRnaSeq.org databases, respectively. Error bars are SEM. Please note the logarithmic y-axis scale in (B). CPM = Counts Per Million; FKPM = Fragments Per Kilobase Million; OPC =

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oligodendrocyte precursor cell; E = embryonic day; P = postnatal day. N.D. = not detected. Please note that receptors that showed an expression level below log1 were considered not expressed (N.E.). (C): Expression of CXCR4 and CX3CR1 mRNA from single-nuclei RNA sequencing analysis of human MS patient brain lesion tissue using the Ki.se/en/mbb/oligointernode database [22]. Data is presented as a heatmap generated in Prism8, where purple has the lowest level of expression and red has the highest level of expression. 23 cell types and the expression level of chemokine receptors are presented across individual rows. Please note that other chemokine receptors discussed in this paper

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were below the detection limit or were not expressed. ImOLGs = Immune

oligodendroglia; VSMCs = vascular smooth muscle cells; Oligo = Oligodendrocyte

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cluster; cOPC = committed OPC.

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Tables.

Table 1. Summary of mutations in neuronal chemokine ligands and cognate receptors in Multiple and Systemic Sclerosis patients. § = Non-coding single nucleotide polymorphism (SNP); # = missense mutation; * = nonsense or frameshift mutation. Coordinates (e.g. -2518) indicate the location of polymorphism as it relates to the transcriptional start site. MS = Multiple Sclerosis; SPMS = secondary progressive

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MS; RRMS = relapse-remitting MS; EDSS = Expanded Disability Status Scale. Mutation

Description (note protective or susceptible)

Reference

CCL2 (MCP-1)

-2518 (A/G) § Susceptible to Systemic Sclerosis  Individuals homozygous for the rs1024611 mutant allele were found in a higher percentage in patients with Systemic Sclerosis (28%) than in controls (6%)

[209, 220]

CCL20

-786 (C/T) § rs6749704

CXCL8 (IL-8)

-251 (A/T) § rs4073

Susceptible  TT genotype is more prevalent in MS patients

[222]

CXCL10 (IP-10)

rs3921 (G/C) Protective §  Progression index was lower in MS patients carrying G/G;T/T (wild-type) rs8878 (T/C) § haplotype as compared with G/C;T/C (Polymorphis or C/C;C/C carriers ms are in 3’untranslated region)

[223]

CCR2

V64I # rs1799864

[224]

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Gene

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Susceptible [221]  Frequency of C/T genotype in CCL20 together with C/T genotype in IL-17F (rs76378) was significantly higher in female MS patients when compared to male MS patients  EDSS was significantly higher in MS patients carrying C/T genotype in CCL20 when compared to MS patients carrying a TT genotype in CCL20

Protective  I64 allele is less frequent in MS

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

patients than controls Not associated with clinical course or severity

CCR5

Δ32 * rs333

Susceptible and protective  MS patients carrying the Δ32 have prolonged time to develop disability and have overall slower disability progression;  Delayed onset of MS with the Δ32 mutation (conflicting reports)  Higher mortality rate in MS patients with the Δ32 mutation

CX3CR1

“V249I” = V322I = V354I # rs3732379

Susceptible and protective [145, 147, 228]  SPMS was significantly higher in V249 homozygous carriers when compared to heterozygous carriers  RRMS was significantly higher in I249 homozygous carriers when compared to heterozygous carriers  I249 homozygous carriers had higher EDSS scores when compared to heterozygous carriers  I249:T280 haplotype was significantly lower in SPMS when compared to RRMS patients  Mice expressing human CX3CR1I249:M280 have more severe EAE, but milder in comparison to CX3CR1 knockout mice

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“T280M” = T312M # rs3732378

[225-227]

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Table 2. Summary of mutations in OPC chemokine receptors in neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD) and Schizophrenia. § = Non-coding single nucleotide polymorphism (SNP); # = missense mutation; * = nonsense or frameshift mutation. Coordinates indicate the location of mutated amino acid (e.g. V64I) or a location of polymorphism as it relates to the transcriptional start site. Name

Mutation

CCR2

V64I # rs1799864



I64 allele was overrepresented in Schizophrenia patients

CCR5

“Δ32” * rs333



[229, 230] Δ32 heterozygous or homozygous genotype was overrepresented in late onset Schizophrenia patients (age at first admission 40 years and older) rs1799987_A/G and G/G genotypes were overrepresented in patients with Schizophrenia CCR2WT:CCR5rs1799987_A and CCR2I64:CCR5rs1799987_A haplotypes were overrepresented in patients with Schizophrenia

V115L = V162L # rs760864060



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V115L or Q25X mutation identified in ASD patients

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CXCR3

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

[229]

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

Reference

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“55029” (A/G) § rs1799987

Description

[231-233]

A55T = A87T # rs750585901 M138I = M170I # rs758302878

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CX3CR1

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Q25X * rs188959001

  

A55T and G112A rare mutations were detected in both ASD and Schizophrenia patients; M138I was detected only in schizophrenia; A55T mutant does not activate Akt signalling when ovexexpressed in HEK293 cells in the presence of CX3CL1 as compared to wild-type CX3CR1.

[210]

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