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

Abstract

Microglia 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, interferon-β, 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.

Keywords: anti-inflammatory treatment; mesenchymal stem cells; microglia; neuroinflammation.

Figure 1

How therapeutic approaches to multiple sclerosis (MS) promote an alternatively activated phenotype in microglia. Both direct and/or indirect effects on microglia have been demonstrated for first-line treatments and for more recent therapeutic approaches to MS. Mechanisms underlying direct effects are mostly unknown, albeit likely to occur through receptor binding such as S1P for fingolimod and CX3CL1/CX3CR1 interaction for mesnechymal stem cells (MSC), and result in modulation of expression and release of anti-inflammatory agents and neuroprotective molecules through signalling via multiple pathways. Indirect effects are mostly related to promotion of an anti-inflammatory environment through down-regulation of antigen-presenting cells (APC) type 1 (pro-inflammatory; APC1) and thereby T helper type 1 (Th1) cells [e.g. dimethyl fumarate (DMF)] and/or fostering APC type 2 (anti-inflammatory; APC2) and thereby Th2 cells [e.g. glatiramer acetate (GA) -specific Th2 cells] that secrete anti-inflammatory cytokines which induce a shift towards an alternatively activated microglial phenotype.