Reduced microglial activation through the inhibition of colony-stimulating factor 1 receptor (CSF1R) to promote remyelination and neuroprotection

VICTORIA SOFÍA BERENICE WIES MANCINI1; JUANA MARÍA PASQUINI1; JORGE DANIEL CORREALE2; LAURA ANDREA PASQUINI1.

París

Congreso; 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017; 2017

ECTRIMS

Background and goals: In recent decades, a better understanding of relapsing-remitting multiple sclerosis (MS) mechanismshas led to the development of several disease-modifying therapies. By contrast, therapeutic options available for progressivedisease are disappointing and remain a challenge. In this context,a 0.2% cuprizone (CPZ) diet administered to adult mice over 5 to6 weeks is known to induce demyelination in the corpus callosum(acute model), with spontaneous remyelination following CPZwithdrawal. A 12-week CPZ diet (chronic model), however, failsto trigger successful remyelination upon CPZ withdrawal, leading to progressive disability. These findings hint at the possibleuse of the CPZ model to develop therapeutic agents enablingremyelination and preventing neurodegeneration. Microglia have03_MSJ731283.indd 49 13/10/2017 9:55:37 AM50 Oral Presentations 23(S3)Multiple Sclerosis Journal 2017; 23: (S3) 8?84 journals.sagepub.com/home/msjbeen 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 adultbrain are physiologically dependent on CSF1R signalling. In thiscontext, the present work proposes the use of the CPZ model totest the potential of CSF1R inhibition as a strategy to stimulateremyelination and/or prevent neurodegeneration by microglialdepletion.Methods: Microglial activation and phenotype were analysedthrough immunohistochemistry (IHC) and flow cytometry assaysusing Iba-1, CD11b and phenotype markers. Demyelination andremyelination were evaluated by MBP IHC and electron microscopy (EM).Results: IHC and EM showed CSF1R inhibition to reducedemyelination in the acute CPZ protocol. IHC also revealed adecrease in microglial activation evaluated by the number ofIba-1+ and iNOS+ cells. Moreover, flow cytometry analyseson the microglial phenotype in selected immunomagneticCD11b+ cells displayed a decrease in the % of CD11b+/CD45+high cells, phagocytic receptor TREM-2 and the numberof CD200+ and TNFα+ cells. In the chronic protocol, inhibitor-treated animals showed less demyelination and enhancedremyelination.Conclusions: These results indicate that CSFR1 inhibitionreduces microglial activation, which protects myelin and ameliorates the need for phagocytosis. Positive results from these experiments could be transferred to the treatment of progressive formsof MS, an urgent and still unmet medical need