Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia

Dong, Yifei; D’Mello, Charlotte; Pinsky, William W.; Lozinski, Brian; Kaushik, Deepak; Ghorbani, Samira; Moezzi, Dorsa; Brown, Dennis; Melo, Francisca C.; Zandee, Stéphanie; Vo, Tina; Prat, Alexandre; Whitehead, Shawn N.; Yong, V. Wee

doi:10.1038/s41593-021-00801-z

Cited by 117 publications

(77 citation statements)

References 60 publications

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“…Prominent depositions of OxPCs are found in white matter lesions in PMS brains and associated with activated microglia. An in vitro study found OxPCs to be toxic to cultured neurons and oligodendroctyes (Dong et al, 2021). The combination of mitochondrial dysfunction, inflammatory metabolites (such as succinate) and inflammatory ROS/RNS may further generate OxPCs, thus contributing to the progression of MS pathology.…”

Section: The Role Of Cell Metabolism and Oxidative Stressmentioning

confidence: 99%

Stem Cell Therapies for Progressive Multiple Sclerosis

Smith¹,

Nicaise

Ionescu

et al. 2021

Front. Cell Dev. Biol.

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal degeneration. MS patients typically present with a relapsing-remitting (RR) disease course, manifesting as sporadic attacks of neurological symptoms including ataxia, fatigue, and sensory impairment. While there are several effective disease-modifying therapies able to address the inflammatory relapses associated with RRMS, most patients will inevitably advance to a progressive disease course marked by a gradual and irreversible accrual of disabilities. Therapeutic intervention in progressive MS (PMS) suffers from a lack of well-characterized biological targets and, hence, a dearth of successful drugs. The few medications approved for the treatment of PMS are typically limited in their efficacy to active forms of the disease, have little impact on slowing degeneration, and fail to promote repair. In looking to address these unmet needs, the multifactorial therapeutic benefits of stem cell therapies are particularly compelling. Ostensibly providing neurotrophic support, immunomodulation and cell replacement, stem cell transplantation holds substantial promise in combatting the complex pathology of chronic neuroinflammation. Herein, we explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and we discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.

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Section: The Role Of Cell Metabolism and Oxidative Stressmentioning

confidence: 99%

Stem Cell Therapies for Progressive Multiple Sclerosis

Smith¹,

Nicaise

Ionescu

et al. 2021

Front. Cell Dev. Biol.

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“…However, especially TAM-MDMs showed elevated expression levels of Trem2/TREM2 in preclinical BrM models or patient material of BrM derived from various primary tumors (Table 2). The contributions of TREM2 and APOE to neurological diseases [e.g., Alzheimer's disease (AD) or multiple sclerosis (MS)] have been extensively described with regard to MG (44,45). Importantly, it was shown that targeting TREM2 + MG represents an interesting approach to attenuate disease progression.…”

Section: Disease-associated Transcriptional Signatures Of Tam-mg In Brmmentioning

confidence: 99%

TAMs in Brain Metastasis: Molecular Signatures in Mouse and Man

Schulz

Sevenich

2021

Front. Immunol.

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Macrophages not only represent an integral part of innate immunity but also critically contribute to tissue and organ homeostasis. Moreover, disease progression is accompanied by macrophage accumulation in many cancer types and is often associated with poor prognosis and therapy resistance. Given their critical role in modulating tumor immunity in primary and metastatic brain cancers, macrophages are emerging as promising therapeutic targets. Different types of macrophages infiltrate brain cancers, including (i) CNS resident macrophages that comprise microglia (TAM-MG) as well as border-associated macrophages and (ii) monocyte-derived macrophages (TAM-MDM) that are recruited from the periphery. Controversy remained about their disease-associated functions since classical approaches did not reliably distinguish between macrophage subpopulations. Recent conceptual and technological advances, such as large-scale omic approaches, provided new insight into molecular profiles of TAMs based on their cellular origin. In this review, we summarize insight from recent studies highlighting similarities and differences of TAM-MG and TAM-MDM at the molecular level. We will focus on data obtained from RNA sequencing and mass cytometry approaches. Together, this knowledge significantly contributes to our understanding of transcriptional and translational programs that define disease-associated TAM functions. Cross-species meta-analyses will further help to evaluate the translational significance of preclinical findings as part of the effort to identify candidates for macrophage-targeted therapy against brain metastasis.

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“…OxPCs were previously described as end-product reporter for oxidative damage and free radical formation in MS lesions ( Haider et al., 2011 ). We recently demonstrated that OxPCs found in MS lesions are mediators of neurodegeneration and that microglia deficiency exacerbates OxPC induced neurodegeneration ( Dong et al., 2021 ). Here, we present protocols for in vitro and in vivo approaches to study microglia functions in response to OxPC mediated neurodegeneration.…”

Section: Expected Outcomesmentioning

confidence: 99%

“…Here, we present protocols including cell isolation and culture, animal surgeries, as well as tissue processing and isolation to study the microglia response to OxPC-mediated neurodegeneration in vitro and in vivo . For complete details on the use and execution of this protocol, please refer to Dong et al. (2021) .…”

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confidence: 99%

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Studying the microglia response to oxidized phosphatidylcholine in primary mouse neuron culture and mouse spinal cord

Dong¹,

Lozinski²,

Yong³

2021

STAR Protocols

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Summary Oxidized phosphatidylcholine (OxPC) found in multiple sclerosis brain lesions mediates neurodegeneration. Microglia are prominent responders to the OxPC insult, and thus, studying their protective or noxious functions is important to help halt neurodegeneration. Here, we present protocols including cell isolation and culture, animal surgeries, as well as tissue processing and isolation to study the microglia response to OxPC-mediated neurodegeneration in vitro and in vivo . For complete details on the use and execution of this protocol, please refer to Dong et al. (2021) .

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Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia

Cited by 117 publications

References 60 publications

Stem Cell Therapies for Progressive Multiple Sclerosis

Stem Cell Therapies for Progressive Multiple Sclerosis

TAMs in Brain Metastasis: Molecular Signatures in Mouse and Man

Studying the microglia response to oxidized phosphatidylcholine in primary mouse neuron culture and mouse spinal cord

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