Review article
Multifaceted aspects of inflammation in multiple sclerosis: The role of microglia

https://doi.org/10.1016/j.jneuroim.2007.09.016Get rights and content

Abstract

The very simplistic view that inflammation in multiple sclerosis (MS) is tout court detrimental has to be profoundly reconsidered. Experimental evidence strongly supports the concept that inflammation in MS is aimed not only at destroying and phagocytosing damaged (infected?) cells (detrimental phase) but also at promoting tissue regeneration or tissue repair via scar formation (resolution or protective phase). Microglia seem to play a crucial role in the different inflammatory phases in MS because they move through multiple functional levels (quantum jumps) either to remove the “danger” signal or to restore the integrity of the central nervous system. The understanding of the molecular signature of any of the quantum microglial states could be useful to better define the cellular and molecular mechanisms underling the different phases of inflammation in MS. This could contribute not only to the design of better therapeutic drugs, but also to the comprehension of the shortcomings of currently used anti-inflammatory drugs.

Introduction

In immune-mediated diseases of the central nervous system (CNS), such as multiple sclerosis (MS), chronic inflammation sustaining disease pathogenesis is usually defined using several different criteria, which are not always overlapping and usually generate misinterpretations. From a clinical point of view, inflammation is superimposed to clinical relapses while gadolinium-enhancing lesions seems to be the only adopted criterion to define inflammation from a neuroradiological point of view. However, inflammation is an immunopathological event encompassing different strategies multi- cellular organisms have evolved to detect and rapidly respond to chemical or physical lesions and to microbial invasion. This process relies on the triggering of specific receptors (e.g. toll-like receptors) able to sense molecules – which are part of the pathogen itself or released from tissues undergoing destruction – acting as danger signals. To activate a first-line defense process, danger signals activate a multi-protein complex called the inflammasome, leading to down stream release of inflammatory mediators (Mariathasan and Monack, 2007). The consequent complex cascade of tissue responses induces the signs that form the classical immunopathological definition of inflammation: rubor, tumor, dolor, calor, functio laesa (Aulus Cornelius Celsus, De medicina).

The very first aim of inflammation is, thus, that of destroying and phagocytosing infected or damaged cells (detrimental phase) to avoid the spread of the pathogen or of the damage to neighboring, healthy, cells. However, a second inflammatory phase usually follows (resolution or protective phase). In this phase, inflammation promotes (at the single cell level or in the tissue) cell survival and tissue rescuing although tissue repair can be also obtained through scar formation. As a matter of fact, several mediators or pathways involved in the two-step inflammatory process show opposite functions depending on the inflammatory phase (Martino, 2004, Martino et al., 2002). Caspase-1, for example, can initiate the apoptotic cascade in some circumstances or promote cell survival in others (Gurcel et al., 2006). The microenvironment (hostile vs. permissive), the nature and the persistence of the insult are among the crucial players in determining the relative contribution of the two different inflammatory phases. Either way, the overall outcome of this double-faced process is protective for the organism and inflammation spontaneously resolves once it has reached its goal through tissue restoration, the so called restitutio ad integrum, or scar formation.

However, there are pathological situations, such as that occurring during MS, in which inflammation fails to spontaneously resolve and tends to persist over time. The persistence of inflammatory detrimental elements in MS renders this disorder chronic in nature so that tissue resolution does not occur. Why inflammation does not resolve in MS? This is thought to depend on an impairment of the inflammatory resolution phase which might be due to a combination of several mechanisms: (i) the abnormal persistence of danger signals in the tissue (virus?), (ii) the development of meningeal ectopic lymphoid aggregates sustaining a compartmentalized chronic autoimmune response (Aloisi and Pujol-Borrell, 2006), (iii) the putative increased resistance of lymphocytes to apotosis (Julia et al., 2006, Sharief et al., 2002), and (iv) the inappropriate and aberrant production in the target tissue of effector lymphocyte pro-retention factors, such as chemokines (e.g. CXCL12), (Krumbholz et al., 2006). Whatever the mechanism(s), we can speculate that in MS the detrimental phase of inflammation overrides the resolution phase.

In the present report we would like to review the role of microglia – which seem to be the culprit of regulating the different phases of inflammation as well as the shift between detrimental and resolution phases – in MS, and in its animal model experimental autoimmune encephalomyelitis (EAE).

Section snippets

What is the macrophage/microglia lineage?

The cell population that has recently emerged as a crucial mediator of CNS inflammation, being able to be activated in different modalities and displaying different functional phenotypes, are microglia. They represent a significant fraction of the adult CNS cells (e.g. 5–20%) (Dobrenis, 1998) and are considered as the CNS equivalent of tissue macrophages. Overall, macrophages and microglia are usually considered as belonging to a unique cell lineage.

There are several ways to classify microglia.

The role of macrophage/microglia lineage in CNS inflammation

Although the exact function of microglia is not fully understood in MS, it has been variably shown that these cells might sustain and propagate inflammation within the CNS during autoimmune inflammation through antigen presentation and/or cytokine/chemokine secretion (Heppner et al., 2005). Microglia located close to the perivascular areas – possibly belonging to the turning over subpopulation of blood-borne microglia/macrophage cells – exert antigen presenting cell (APC) function on myelin-

The role of macrophage/microglia lineage in inflammatory demyelination and remyelination

The pathological hallmarks of MS are multiple demyelinated lesions disseminated throughout the white matter of the CNS. Lesions are characterized by inflammatory demyelination, ultimately leading to gliosis and axonal damage (Martino, 2004). As previously mentioned, the prevalent view is that demyelination in MS is caused by CNS-invading blood borne cells which, along with resident activated microglia cells, sustain inflammation and instruct macrophages/microglia to phagocytose myelin and

The role of macrophage/microglia lineage in inflammatory-induced plasticity

Synaptic plasticity is one of the most efficient strategies the brain contemplates to respond to lesions causing functional damage. Re-organizing cortical areas is a precocious event also in MS (Rocca et al., 2005). Modulation of synaptic activity and synaptogenesis are the two main features of synaptic plasticity. While the driving force of this process is unknown in humans, experimental data point out a possible role for pro- inflammatory cytokines released by macrophage/microglia-like cells.

Quantum jumps of microglia: a new perspective

The data reviewed here support the idea that microglia may play a crucial role in the development of autoimmune chronic inflammatory processes such as those characterizing MS and its animal model EAE. Although not yet conclusive, a possible scenario involving microglia as the culprit in MS can be envisaged. Perivascular microglia alert parenchymal microglia about potential danger signals they sense in the perivascular space generated by infiltrating blood-borne inflammatory cells (Fig. 1A). As

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