Inflammation in the Pathogenesis of Inherited Peripheral Neuropathies

Groh, Janos; Klein, Dennis; Kroner, Antje; Martini, Rudolf

doi:10.1002/9781118732748.ch8

Cited by 5 publications

(6 citation statements)

References 87 publications

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“…That innate immune cells are involved in the disease development and progression of genetically mediated myelin disorders has initially been described for the peripheral nervous system (Groh, Klein, Kroner, & Martini, ; Klein & Martini, ; Martini & Willison, ). Based on genetic studies in models mimicking distinct Charcot–Marie‐Tooth (CMT) disorders, we could show that the secreted proteoglycan isoform of the cytokine CSF‐1 is a leading activator of pathogenic peripheral nerve macrophages that not only phagocytose myelin, but also promote Schwann cell dedifferentiation, likely affecting axon function and integrity (Groh, Basu, Stanley, & Martini, ; Groh et al, ; Groh et al, ).…”

Section: Discussionmentioning

confidence: 99%

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Groh

Klein

Berve

et al. 2018

Glia

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Genetically caused neurological disorders of the central nervous system (CNS) usually result in poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with disease‐amplifying neuroinflammation, a feature shared by progressive forms of multiple sclerosis (PMS), another poorly treatable disorder of the CNS. We have previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients fulfilling clinical criteria for multiple sclerosis (MS). These mutations cause a loss of function of the gene product resulting in a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation comprising adaptive immune reactions promotes disease progression in these PLP1 mutant models, opening the possibility to improve disease outcome of the respective disorders by targeting/modulating inflammation. We here show that PLX3397, a potent inhibitor of the CSF‐1R and targeting innate immune cells, attenuates neuroinflammation in our models by reducing numbers of resident microglia and attenuating T‐lymphocyte recruitment in the CNS. This leads to an amelioration of demyelination, axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the inner retinal composite layer in longitudinal studies using noninvasive optical coherence tomography. Our findings identify microglia as important promoters of neuroinflammation‐related neural damage and CSF‐1R inhibition as a possible therapeutic strategy not only for PMS but also for inflammation‐related genetic diseases of the nervous system for which causal treatment options are presently lacking.

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Section: Discussionmentioning

confidence: 99%

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Groh

Klein

Berve

et al. 2018

Glia

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“…This forms inflammatory demyelinating neuritis and further develops into Bell's palsy. Animal experiments on neuropathology have shown that inactivation or knockout of CSF1 results in sustained and significant improvement in peripheral nerve damage in mice, including the facial nerve (Carenini et al, ; Groh, Klein, Kroner, & Martini, ; Groh et al, ). Therefore, if the activity of CSF1 can be prevented in time, in the early stage of Bell's palsy, it may be beneficial to the early recovery of Bell's palsy.…”

Section: Discussionmentioning

confidence: 99%

Immune‐related gene expression profiles of hypothermia adipocytes: Implications for Bell's palsy

Zhang

Luo

et al. 2019

Oral Diseases

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Objective To identify immune‐related gene expression profiles of adipocytes under low temperatures with RNA sequencing as a model for Bell's palsy implications. Methods Adipocytes were harvested from the white adipose tissue of male Sprague‐Dawley rats and cultured under different acute‐grade cold exposure conditions of 30, 20, and 10°C, and their genomes were sequenced for RNA sequencing analysis. The differentially expressed genes (DEGs) were validated with reverse transcription polymerase chain reaction. Results In total, 55 (35 upregulated and 20 downregulated), 121 (76 upregulated and 45 downregulated), and 92 (64 upregulated and 28 downregulated) DEGs were identified under 30, 20, and 10°C compared with the control, respectively. KEGG and GO analysis revealed that the DEGs were considerably enriched in immune‐related pathways (leukocyte transendothelial migration and platelet activation) and infection (bacterial invasion of epithelial cells and Salmonella infection). The levels of key inflammatory chemokines (CSF1, CXCL1, CCL2, and CCL7) were enhanced after cold exposure. Conclusion These findings broaden our understanding of the immune responses to cold exposure in adipocytes. The molecular profiles of adipocyte immune function will help clarify the potential mechanism impacting myelin, which might contribute to the development of strategies to control Bell's palsy.

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“…In models mimicking CMT1A (most common), CMT1X (second most common), and CMT1B (third most common), achieved by mild overexpression of peripheral myelin protein 22 (PMP22tg mice; Huxley et al, ), deficiency for connexin 32 (Cx32def mice; Anzini et al, ) and heterozygous deficiency for myelin protein zero (P0het mice; Giese et al, ; Martini et al, ), respectively, the mutations in these mice cause some characteristic, dedifferentiation‐related features typical for each model (Klein et al, ). However, there are also remarkable similarities among the distinct mutants, with inflammation being a pathomechanistic commonality determining the ultimate outcome of the disease (Groh et al, ).…”

Section: Models For Inherited Peripheral Neuropathies As Paradigm Formentioning

confidence: 99%

Neuroinflammation in the peripheral nerve: Cause, modulator, or bystander in peripheral neuropathies?

Martini

Willison

2015

Glia

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The role of innate and adaptive inflammation as a primary driver or modifier of neuropathy in premorbidly normal nerves, and as a critical player in amplifying neuropathies of other known causes (e.g., genetic, metabolic) is incompletely understood and under‐researched, despite unmet clinical need. Also, cellular and humoral components of the adaptive and innate immune system are substantial disease modifying agents in the context of neuropathies and, at least in some neuropathies, there is an identified tight interrelationship between both compartments of the immune system. Additionally, the quadruple relationship between Schwann cell, axon, macrophage, and endoneurial fibroblast, with their diverse membrane bound and soluble signalling systems, forms a distinct focus for investigation in nerve diseases with inflammation secondary to Schwann cell mutations and possibly others. Identification of key immunological effector pathways that amplify neuropathic features and associated clinical symptomatology including pain should lead to realistic and timely possibilities for translatable therapeutic interventions using existing immunomodulators, alongside the development of novel therapeutic targets. GLIA 2016;64:475–486

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Inflammation in the Pathogenesis of Inherited Peripheral Neuropathies

Cited by 5 publications

References 87 publications

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Immune‐related gene expression profiles of hypothermia adipocytes: Implications for Bell's palsy

Neuroinflammation in the peripheral nerve: Cause, modulator, or bystander in peripheral neuropathies?

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