Can we switch microglia's phenotype to foster neuroprotection? Focus on multiple sclerosis

Abstract

OTHER ARTICLES PUBLISHED IN THIS SERIES SummaryMicroglia cells, the resident innate immune cells in the brain, are highly active, extending and retracting highly motile processes through which they continuously survey their microenvironment for 'danger signals' and interact dynamically with surrounding cells. Upon sensing changes in their central nervous system microenvironment, microglia become activated, undergoing morphological and functional changes. Microglia activation is not an 'all-or-none' process, but rather a continuum depending on encountered stimuli, which is expressed through a spectrum of molecular and functional phenotypes ranging from so-called 'classically activated', with a highly pro-inflammatory profile, to 'alternatively activated' associated with a beneficial, less inflammatory, neuroprotective profile. Microglia activation has been demonstrated in most neurological diseases of diverse aetiology and has been implicated as a contributor to neurodegeneration. The possibility to promote microglia's neuroprotective phenotype has therefore become a therapeutic goal. We have focused our discussion on the role of microglia in multiple sclerosis, a prototype of inflammatory, demyelinating, neurodegenerative disease, and on the effect of currently approved or on-trial anti-inflammatory therapeutic strategies that might mediate neuroprotection at least in part through their effect on microglia by modifying their behaviour via a switch of their functional phenotype from a detrimental to a protective one. In addition to pharmaceutical approaches, such as treatment with glatiramer acetate, interferonb, fingolimod or dimethyl fumarate, we address the alternative therapeutic approach of treatment with mesenchymal stem cells and their potential role in neuroprotection through their 'calming' effect on microglia.

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…To date, the examination of immunomodulatory agents on microglial activation has been limited to preclinical and postmortem human studies (51)(52)(53). A potential application of the [ 11 C]PBR28-LPS model is to test medications designed to temper neuroinflammation, e.g., the neuroinflammation implicated in early onset (<65 y old) Alzheimer's disease (22).…”

Mesenchymal stem cells for the treatment of neurological diseases: Immunoregulation beyond neuroprotection

“…In vitro, MSCs affect also the behavior of CNS cells such as microglial cells, and particularly inhibit microglial proliferation and their release of proinflammatory molecules; more specifically, MSCs induce the release of neuroprotective molecules by microglia and increase their phagocytic capability through the release of soluble factors [30][31][32][33][34][35]. Similarly, MSCs are able to skew the phenotype of macrophages from M1 to M2 type [36] [37].…”

Neuroprotective therapies for multiple sclerosis and other demyelinating diseases

“…apoptosis, energetic supply, ionic balance) have been mimicked with experimental therapies [3,11]. In addition, several regenerative therapies, such as stem cells, may provide some benefits via neuroprotective effects, including the release of trophic factors, suppressing local inflammation or promoting a microenvironment supporting the survival of neurons, axons and oligodendrocytes [12]. Finally, secondary neuroprotection can be achieved by the reduction of the insult such as restoring blood supply in ischemia, decreasing excitotoxicity by reducing epileptogenic activity in seizures or decreasing CNS inflammation with the use of immunomodulatory drugs (e.g.…”

“…Finally, it is well known that glia, including astrocytes and microglia, can display neuroprotective activities, although many of them are poorly understood [12,55]. For example, healthy neurons express CD200, which interacts with CD200L promoting survival signals [56].…”