Reduced microglial activation through the inhibition of colony-stimulating factor 1 receptor (CSF1R) to promote remyelination and neuroprotection
ECTRIMS Online Library. Correale J. 10/27/17; 202540; 182
Jorge Correale
Jorge Correale
Contributions
Abstract

Abstract: 182

Type: Oral

Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models

Background and goals: In recent decades, a better understanding of relapsing-remitting multiple sclerosis (MS) mechanisms has led to the development of several disease-modifying therapies. By contrast, therapeutic options available for progressive disease are disappointing and remain a challenge. In this context, a 0.2% cuprizone (CPZ) diet administered to adult mice over 5 to 6 weeks is known to induce demyelination in the corpus callosum (acute model), with spontaneous remyelination following CPZ withdrawal. A 12-week CPZ diet (chronic model), however, fails to trigger successful remyelination upon CPZ withdrawal, leading to progressive disability. These findings hint at the possible use of the CPZ model to develop therapeutic agents enabling remyelination and preventing neurodegeneration. Microglia have been shown to actively participate in demyelination and neurodegeneration. In addition, the inhibition of colony-stimulating factor 1 receptor (CSF1R) results in the elimination of ~99% microglia brain-wide, showing that microglial cells in the adult brain are physiologically dependent on CSF1R signalling. In this context, the present work proposes the use of the CPZ model to test the potential of CSF1R inhibition as a strategy to stimulate remyelination and/or prevent neurodegeneration by microglial depletion.
Methods: Microglial activation and phenotype were analysed through immunohistochemistry (IHC) and flow cytometry assays using Iba-1, CD11b and phenotype markers. Demyelination and remyelination were evaluated by MBP IHC and electron microscopy (EM).
Results: IHC and EM showed CSF1R inhibition to reduce demyelination in the acute CPZ protocol. IHC also revealed a decrease in microglial activation evaluated by the number of Iba-1+ and iNOS+ cells. Moreover, flow cytometry analyses on the microglial phenotype in selected immunomagnetic CD11b+ cells displayed a decrease in the % of CD11b+/CD45+high cells, phagocytic receptor TREM-2 and the number of CD200+ and TNFα+ cells. In the chronic protocol, inhibitor-treated animals showed less demyelination and enhanced remyelination.
Conclusions: These results indicate that CSFR1 inhibition reduces microglial activation, which protects myelin and ameliorates the need for phagocytosis. Positive results from these experiments could be transferred to the treatment of progressive forms of MS, an urgent and still unmet medical need.
Disclosure:
Victoria Wies Mancini: Nothing to disclose
Juana MAria Pasquini: Nothing to disclose
Laura Andrea Pasquini: Nothing to disclose
Jorge Correale: Dr. Correale is a board member of Merck-Serono Argentina, Biogen-Idec LATAM, and Merck-Serono LATAM, and Genzyme global. Dr Correale is a board member of Merck-Serono Argentina, Novartis Argentina, Genzyme LATAM, Genzyme global, Biogen-Idec LATAM, and Merck-Serono LATAM. He is part of the Steering Committee for the clinical trials of Ofatumumab (Novartis Global). Dr. Correale has received reimbursement for developing educational presentations for Merck-Serono Argentina, Merck-Serono LATAM, Biogen-Idec Argentina, Genzyme Argentina, Novartis Argentina, Novartis LATAM, Novartis Global, and TEVA Argentina as well as professional travel/accommodations stipends.

Abstract: 182

Type: Oral

Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models

Background and goals: In recent decades, a better understanding of relapsing-remitting multiple sclerosis (MS) mechanisms has led to the development of several disease-modifying therapies. By contrast, therapeutic options available for progressive disease are disappointing and remain a challenge. In this context, a 0.2% cuprizone (CPZ) diet administered to adult mice over 5 to 6 weeks is known to induce demyelination in the corpus callosum (acute model), with spontaneous remyelination following CPZ withdrawal. A 12-week CPZ diet (chronic model), however, fails to trigger successful remyelination upon CPZ withdrawal, leading to progressive disability. These findings hint at the possible use of the CPZ model to develop therapeutic agents enabling remyelination and preventing neurodegeneration. Microglia have been shown to actively participate in demyelination and neurodegeneration. In addition, the inhibition of colony-stimulating factor 1 receptor (CSF1R) results in the elimination of ~99% microglia brain-wide, showing that microglial cells in the adult brain are physiologically dependent on CSF1R signalling. In this context, the present work proposes the use of the CPZ model to test the potential of CSF1R inhibition as a strategy to stimulate remyelination and/or prevent neurodegeneration by microglial depletion.
Methods: Microglial activation and phenotype were analysed through immunohistochemistry (IHC) and flow cytometry assays using Iba-1, CD11b and phenotype markers. Demyelination and remyelination were evaluated by MBP IHC and electron microscopy (EM).
Results: IHC and EM showed CSF1R inhibition to reduce demyelination in the acute CPZ protocol. IHC also revealed a decrease in microglial activation evaluated by the number of Iba-1+ and iNOS+ cells. Moreover, flow cytometry analyses on the microglial phenotype in selected immunomagnetic CD11b+ cells displayed a decrease in the % of CD11b+/CD45+high cells, phagocytic receptor TREM-2 and the number of CD200+ and TNFα+ cells. In the chronic protocol, inhibitor-treated animals showed less demyelination and enhanced remyelination.
Conclusions: These results indicate that CSFR1 inhibition reduces microglial activation, which protects myelin and ameliorates the need for phagocytosis. Positive results from these experiments could be transferred to the treatment of progressive forms of MS, an urgent and still unmet medical need.
Disclosure:
Victoria Wies Mancini: Nothing to disclose
Juana MAria Pasquini: Nothing to disclose
Laura Andrea Pasquini: Nothing to disclose
Jorge Correale: Dr. Correale is a board member of Merck-Serono Argentina, Biogen-Idec LATAM, and Merck-Serono LATAM, and Genzyme global. Dr Correale is a board member of Merck-Serono Argentina, Novartis Argentina, Genzyme LATAM, Genzyme global, Biogen-Idec LATAM, and Merck-Serono LATAM. He is part of the Steering Committee for the clinical trials of Ofatumumab (Novartis Global). Dr. Correale has received reimbursement for developing educational presentations for Merck-Serono Argentina, Merck-Serono LATAM, Biogen-Idec Argentina, Genzyme Argentina, Novartis Argentina, Novartis LATAM, Novartis Global, and TEVA Argentina as well as professional travel/accommodations stipends.

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