Increased <i>Plp1</i> Gene Expression Leads to Massive Microglial Cell Activation and Inflammation Throughout the Brain

Tatar, Carrie Lynn; Appikatla, Sunita; Bessert, Denise; Paintlia, Ajaib S.; Singh, Inderjit; Skoff, Robert P.

doi:10.1042/an20100016

Cited by 50 publications

(62 citation statements)

References 71 publications

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“…Skoff and colleagues [22] have previously demonstrated microglia / macrophage activation in adult homozygous Plp1#66 mice and our data are consistent with their findings. In heterozygous Plp1 #66 mice, microglia / macrophages are similar to wild type (not shown) with small cell bodies, although the processes show some thickening and are not extensively ramified.…”

Section: Resultssupporting

confidence: 93%

“…In contrast, other studies have observed significant numbers of peripheral immune cells in Plp1 mutants, with the most detailed analysis performed on Plp1 overexpressor mice, but these animals were 5 – 12 months of age [32]. Tatar and colleagues [22] also observed an age-dependent increase in immune activation, which may account for the relatively mild level of immune activation in msd mice, which were P16. Unfortunately, the lifespan of these mutants is 3 – 4 weeks, which may be insufficient time for robust immune responses such as CNS invasion by peripherally activated T and/or B cells.…”

Section: Resultsmentioning

confidence: 99%

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Potential for Cell-Mediated Immune Responses in Mouse Models of Pelizaeus-Merzbacher Disease

et al. 2013

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Although activation of the innate and adaptive arms of the immune system are undoubtedly involved in the pathophysiology of neurodegenerative diseases, it is unclear whether immune system activation is a primary or secondary event. Increasingly, published studies link primary metabolic stress to secondary inflammatory responses inside and outside of the nervous system. In this study, we show that the metabolic stress pathway known as the unfolded protein response (UPR) leads to secondary activation of the immune system. First, we observe innate immune system activation in autopsy specimens from Pelizaeus-Merzbacher disease (PMD) patients and mouse models stemming from PLP1 gene mutations. Second, missense mutations in mildly- and severely-affected Plp1-mutant mice exhibit immune-associated expression profiles with greater disease severity causing an increasingly proinflammatory environment. Third and unexpectedly, we find little evidence for dysregulated expression of major antioxidant pathways, suggesting that the unfolded protein and oxidative stress responses are separable. Together, these data show that UPR activation can precede innate and/or adaptive immune system activation and that neuroinflammation can be titrated by metabolic stress in oligodendrocytes. Whether-or-not such activation leads to autoimmune disease in humans is unclear, but the case report of steroid-mitigated symptoms in a PMD patient initially diagnosed with multiple sclerosis lends support.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Potential for Cell-Mediated Immune Responses in Mouse Models of Pelizaeus-Merzbacher Disease

et al. 2013

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“…The basis for this conclusion was reasonable as PMD is an inherited disorder with its origins in the CNS. More recently, transgenic mice with an increased copy number of native Plp1 were shown to have extensive microglial activity and up-regulation of two pro-inflammatory markers as based upon message levels, TNF-α and IL-6 [53]. The wide spread activation of multiple cytokines and chemokines, presumably produced mainly by microglia and astrocytes, is likely a response to several factors including the demyelination and insertion of PLP into mitochondria when the gene is duplicated [3].…”

Section: Discussionmentioning

confidence: 99%

Novel pathologic findings in patients with Pelizaeus-Merzbacher disease

Laukka

Kamholz

Bessert

et al. 2016

Neuroscience Letters

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Pelizaeus-Merzbacher disease (PMD) is an X-linked inherited hypomyelinating disorder caused by mutations in the gene encoding proteolipid protein (PLP), the major structural protein in central nervous system (CNS) myelin. Prior to our study, whether hypomyelination in PMD was caused by demyelination, abnormally thin sheaths or failure to form myelin was unknown. In this study, we compared the microscopic pathology of myelin from brain tissue of 3 PMD patients with PLP1 duplications to that of a patient with a complete PLP1 deletion. Autopsy tissue procured from PMD patients was embedded in paraffin for immunocytochemistry and plastic for electron microscopy to obtain highresolution fiber pathology of cerebrum and corpus callosum. Through histological stains, immunocytochemistry and electron microscopy, our study illustrates unique pathologic findings between the two different types of mutations. Characteristic of the patient with a PLP1 deletion, myelin sheaths showed splitting and decompaction of myelin, confirming for the first time that myelin in PLP1 deletion patients is similar to that of rodent models with gene deletions. Myelin thickness and g-ratios of some fibers, in relation to axon diameter was abnormally thin, suggesting that oligodendrocytes remain metabolically functional and/or are attempting to make myelin. Many fibers showed swollen, progressive degenerative changes to axons in addition to the dissolution of myelin. All three duplication cases shared remarkable fiber pathology including swellings, constriction and/or transection and involution of myelin. Characteristic of PLP1 duplication patients, many axons showed segmental demyelination along their length. Still other axons had abnormally thick myelin sheaths, suggestive of continued myelination. Thus, each type of mutation exhibited unique pathology even though commonality to both mutations included involution of myelin, myelin balls and degeneration of axons. This pathology study describes findings unique to each mutation that suggests the mechanism causing fiber pathology is likewise heterogeneous.

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“…Furthermore, the importance of chemokines has been demonstrated in other diseases that are characterized by myelin abnormalities and/or oligodendrocyte pathology, including amyotrophic lateral sclerosis (27), Alzheimer's disease (28), leukodystrophies (29), or schizophrenia (30).…”

mentioning

confidence: 99%

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

Clarner

Janssen

Nellessen

et al. 2015

The Journal of Immunology

118

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A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.

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Increased Plp1 Gene Expression Leads to Massive Microglial Cell Activation and Inflammation Throughout the Brain

Cited by 50 publications

References 71 publications

Potential for Cell-Mediated Immune Responses in Mouse Models of Pelizaeus-Merzbacher Disease

Potential for Cell-Mediated Immune Responses in Mouse Models of Pelizaeus-Merzbacher Disease

Novel pathologic findings in patients with Pelizaeus-Merzbacher disease

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

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