Polarization of microglia in neurodegenerative diseases


MS and brain ischemia have a robust inflammatory component. Microglia are representatives of the innate immune system. The microglial phenotype is viewed as being dichotomous, whereby ‘resting’ microglia are converted upon stimulation into a ‘classically activated’ state termed M1 activation, which is associated with the expression of pro-inflammatory molecules. Recently microglia/macrophages were shown to be heterogeneous with respect to activation status, exhibiting a spectrum of diverse and plastic phenotypes including those associated with tissue maintenance and repair, known as “alternative” (M2) activation. Partner 6 plans to study the M1 and M2 activation states of the microglia in neuroinflammation associated with MS and brain ischemia in collaboration with partners 1, 11, and 15. Astrocyte and microglia activation will be investigated in glia-neuron co-cultures and animal models of MS and brain ischemia. The development of in vivo imaging technique and novel molecular probes for inflammation will be associated to qRT-PCR, Western blot and ELISA analyses of inflammatory markers. Fluorescent analysis of activation markers will help to define microglial polarization. Adult and neonatal mice subjected to brain ischemia will be studied in the acute as well as in the subacute phase of disease. In order to modulate microglial polarization recent experience from partners 6 and 11 will be used. Partner 6 has found that two epigenetic drugs are able to elicit a sustained and synergistic neuroprotection in mouse stroke, even when administered 7 h after the ischemic insult. Partner 11 has recently developed new NSAID-derivatives (e.g., CHF5074) endowed with neuroprotective activity. Innovative combinations of epigenetic drugs together with CHF5074 will be investigated for their capability to switch microglial activation from M1 toward M2. The epigenetic machinery responsible for M1 and M2 phenotypes will be investigated by chromatin immunoprecipitation of histones and transcription factors interacting with cytokine gene promoters. The therapeutic efficacy will be analyzed by tests of neurological deficits, including rotarod and Catwalk gait analysis. The aim will be to identify new cellular and molecular targets for neuroprotection and test novel therapeutic strategies.


    • Lanzillotta A, Pignataro G, Branca C, Cuomo O, Sarnico I, Benarese M, Annunziato L, Spano P, Pizzi M (2013) Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window.Neurobiol Dis 49: 177–189
    • Valerio A, Dossena M, Bertolotti P, Boroni F, Sarnico I, Faraco G, Chiarugi A, Frontini A, Giordano A, Liou HC, De Simoni MG, Spano P, Carruba MO, Pizzi M *, Nisoli E * Leptin is induced in ischemic cerebral cortex and exerts neuroprotection via NF-kB/c-Rel-dependent transcription. Stroke 40: 610-617, * contributed equally

    Tasks and methodology

      • Glial-neuron co-cultures
      • Mouse models of MS and stroke
      • Chromatin immunoprecipitation asssays, Western blotting, immunofluorescence analysis, ELISA assays, quantitative RT-PCR

      Planned secondment

      University of Bologna, Chiesi Farrnaceutici S.P.A., Microglial polarization in in vivo models, 10 month

      Host Organisation:
      Department of molecular and translational medicine
      Marina Pizzi
      Arianna Bellucci, Annamaria Lanzillotta, University of Brescia
      Early Stage Researcher: