CXCR2 Signaling and Remyelination in Preclinical Models of Demyelination

Skinner, Dominic D; Lane, Thomas E.

doi:10.1089/dna.2019.5182

Cited by 7 publications

(3 citation statements)

References 47 publications

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“…As cause for such dysregulated gene expression in OLGs, recent evidence points to the actions of extrinsic factors rather than intrinsic OLG defects (Golan et al, 2021; Kirby et al, 2019; Mozafari et al, 2020; Saraswat et al, 2021; Starost et al, 2020). Thus, targeting druggable signaling pathways with the capacity to modulate gene expression profiles associated with OLG maturation has emerged as a promising approach toward promoting repair of the myelin sheath in MS (Angelini et al, 2021; Gaesser & Fyffe‐Maricich, 2016; Göttle et al, 2019; Green et al, 2017; Jeffries et al, 2016, 2021; Lecca et al, 2020; Mausner‐Fainberg et al, 2021; Mierzwa et al, 2013; Petersen et al, 2021; Rajendran et al, 2021; Roggeri et al, 2020; Skinner & Lane, 2020; Thümmler et al, 2019; Wang et al, 2020; Welliver et al, 2018). Despite an increasing number of potential pathways with promyelinating characteristics, however, clinical translation has, up until now, been below expectation (Abu‐Rub & Miller, 2018; Lubetzki et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation

Spencer

Suárez-Pozos

Soto-Verdugo

et al. 2022

Journal of Neurochemistry

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The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G proteincoupled receptor LPA 6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA 6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA 6 and LPA 6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA 6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA 6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA 6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA 6 protein levels appear | 479 SPENCER et al.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation

Spencer

Suárez-Pozos

Soto-Verdugo

et al. 2022

Journal of Neurochemistry

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“…Oxysterols can activate another Gi protein-coupled receptor, CXCR2, which is important for cell migration to the site of infl ammation. In the brain, CXCR2 expression in the microglia, oligodendrocytes, and neurons is upregulated upon injury, and the activation of CXCR2 can negatively control myelination, as well as disrupt excitatory neurotransmission [63,64]. However, 25-HC (unlike 22R-HC) is a weak agonist of CXCR2 even at high concentrations [65].…”

Section: Hydroxycholesterol As a Molecule Of Intercellular Interacti...mentioning

confidence: 99%

25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Odnoshivkina

Kuznetsova

Petrov

2022

Biochemistry Moscow

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Cholesterol is an essential component of plasma membrane and precursor of biological active compounds, including hydroxycholesterols (HCs). HCs regulate cellular homeostasis of cholesterol; they can pass across the membrane and vascular barriers and act distantly as para-and endocrine agents. A small amount of 25-hydroxycholesterol (25-HC) is produced in the endoplasmic reticulum of most cells, where it serves as a potent regulator of the synthesis, intracellular transport, and storage of cholesterol. Production of 25-HC is strongly increased in the macrophages, dendrite cells, and microglia at the infl ammatory response. The synthesis of 25-HC can be also upregulated in some neurological disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, spastic paraplegia type 5, and X-linked adrenoleukodystrophy. However, it is unclear whether 25-HC aggravates these pathologies or has the protective properties. The molecular targets for 25-HC are transcriptional factors (LX receptors, SREBP2, ROR), G protein-coupled receptor (GPR183), ion channels (NMDA receptors, SLO1), adhesive molecules (α5β1 and ανβ3 integrins), and oxysterol-binding proteins. The diversity of 25-HC-binding proteins points to the ability of HC to aff ect many physiological and pathological processes. In this review, we focused on the regulation of 25-HC production and its universal role in the control of cellular cholesterol homeostasis, as well as the eff ects of 25-HC as a signaling molecule mediating the infl uence of infl ammation on the processes in the neuromuscular system and brain. Based on the evidence collected, it can be suggested that 25-HC prevents accumulation of cellular cholesterol and serves as a potent modulator of neuroinfl ammation, synaptic transmission, and myelinization. An increased production of 25-HC in response to a various type of damage can have a protective role and reduce neuronal loss. At the same time, an excess of 25-HC may exert the neurotoxic eff ects.

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“…Moreover, microglia and macrophages have been shown to mediate demyelination (Savarin et al, 2016 ). This overt demyelination lends itself to elegant remyelination studies as chemokines like CXCR2 are highly upregulated and are critical to OPC-mediated repair (Marro et al, 2019 ; Skinner and Lane, 2020 ). Despite an overall reduction in T cells during viral persistence, new lesions are continuously formed as shown by lipid laden myeloid cells (Wu et al, 2000 ; Liu et al, 2001 ; Rempel et al, 2004 ), consistent with MS lesions.…”

Section: Murine Models Of Msmentioning

confidence: 99%

Connecting Neuroinflammation and Neurodegeneration in Multiple Sclerosis: Are Oligodendrocyte Precursor Cells a Nexus of Disease?

Psenicka

Smith

Tinkey

et al. 2021

Front. Cell. Neurosci.

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The pathology in neurodegenerative diseases is often accompanied by inflammation. It is well-known that many cells within the central nervous system (CNS) also contribute to ongoing neuroinflammation, which can promote neurodegeneration. Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease in which there is a complex interplay between resident CNS cells to mediate myelin and axonal damage, and this communication network can vary depending on the subtype and chronicity of disease. Oligodendrocytes, the myelinating cell of the CNS, and their precursors, oligodendrocyte precursor cells (OPCs), are often thought of as the targets of autoimmune pathology during MS and in several animal models of MS; however, there is emerging evidence that OPCs actively contribute to inflammation that directly and indirectly contributes to neurodegeneration. Here we discuss several contributors to MS disease progression starting with lesion pathology and murine models amenable to studying particular aspects of disease. We then review how OPCs themselves can play an active role in promoting neuroinflammation and neurodegeneration, and how other resident CNS cells including microglia, astrocytes, and neurons can impact OPC function. Further, we outline the very complex and pleiotropic role(s) of several inflammatory cytokines and other secreted factors classically described as solely deleterious during MS and its animal models, but in fact, have many neuroprotective functions and promote a return to homeostasis, in part via modulation of OPC function. Finally, since MS affects patients from the onset of disease throughout their lifespan, we discuss the impact of aging on OPC function and CNS recovery. It is becoming clear that OPCs are not simply a bystander during MS progression and uncovering the active roles they play during different stages of disease will help uncover potential new avenues for therapeutic intervention.

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CXCR2 Signaling and Remyelination in Preclinical Models of Demyelination

Cited by 7 publications

References 47 publications

Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation

Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation

25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Connecting Neuroinflammation and Neurodegeneration in Multiple Sclerosis: Are Oligodendrocyte Precursor Cells a Nexus of Disease?

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CXCR2 Signaling and Remyelination in Preclinical Models of Demyelination

Cited by 7 publications

References 47 publications

Lysophosphatidic acid signaling via LPA6: A negative modulator of developmental oligodendrocyte maturation

Lysophosphatidic acid signaling via LPA6: A negative modulator of developmental oligodendrocyte maturation

25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Connecting Neuroinflammation and Neurodegeneration in Multiple Sclerosis: Are Oligodendrocyte Precursor Cells a Nexus of Disease?

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Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation

Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation