revue neurologique 165 (2009) 1023–1028
Journe´e du Pre´sident – Novembre 2008
Neuroinflammation responses and neurodegeneration in multiple sclerosis Physiopathologie de la scle´rose en plaques : neuroinflammation(s) et neurode´ge´ne´rescence S. Nataf a,b a b
Inserm U842, faculte´ Laennec, 7, rue Guillaume-Pardin, 69372 Lyon cedex 8, France University of Lyon, hospices Civils de Lyon, France
Diffuse neurodegeneration is now considered to be the main cause of irreversible neuro-
Published on line 10 November 2009
logical disability in multiple sclerosis (MS). Demonstration of a diffuse inflammatory reaction in the MS brain led to the assumption that diffuse neuroinflammation induces
diffuse neurodegeneration. Macrophages/microglia accumulate throughout the MS brain
and are, therefore, considered the main culprits implicated in the development of neuro-
degeneration. However, recent advances in the understanding of macrophage/microglia
functions and origins have now challenged that view. This report is a summary of these
advances, and discusses their contribution to the perception of macrophage/microglia
functions in MS-associated neurodegeneration. # 2009 Elsevier Masson SAS. All rights reserved.
Mots cle´s : Microglie Macrophages
r e´ s u m e´
Scle´rose en plaques Neuroinflammation
Chez les patients atteints de scle´rose en plaques (SEP), la perte axonale diffuse est actuel-
lement conside´re´e comme l’e´le´ment causal majeur du handicap neurologique irre´versible. La mise en e´vidence d’une neuroinflammation diffuse dans le cerveau des patients SEP sugge`re un lien direct entre neuroinflammation et neurode´ge´ne´rescence diffuse. Dans ce contexte, la microglie et les macrophages, dont l’accumulation au cours de la SEP est observe´e dans l’ensemble du syste`me nerveux central, sont conside´re´s comme les principaux suspects implique´s dans la perte axonale diffuse. Des e´le´ments bibliographiques re´cents concernant l’origine et les fonctions macrophagiques/microgliales indiquent ne´anmoins que ce sche´ma physiopathologique est inexact ou pour le moins incomplet. La pre´sente revue re´sume ces nouvelles donne´es et discute leur contribution a` la compre´hension des liens entre macrophages/microglie et neurode´ge´ne´rescence. # 2009 Elsevier Masson SAS. Tous droits re´serve´s.
E-mail address: [email protected]
0035-3787/$ – see front matter # 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neurol.2009.09.012
revue neurologique 165 (2009) 1023–1028
Multiple sclerosis (MS) has long been defined as a chronic inflammatory and demyelinating disease of the central nervous system (CNS). However, diffuse neurodegeneration characterized by diffuse axonal loss is now recognized to be an important feature of MS neuropathology and a major cause of irreversible neurological disability (Bjartmar et al., 2000; Confavreux and Compston, 2006; Confavreux and Vukusic, 2006). Demonstration of a diffuse inflammatory reaction in the normal-appearing white matter in patients with progressive MS led to the assumption that diffuse neuroinflammation induces diffuse neurodegeneration (Kutzelnigg et al., 2005; Frischer et al., 2009). As a consequence, macrophages/ microglia, which accumulate throughout the CNS of MS patients, were considered the main culprits implicated in the development of neurodegeneration. In support of this view, numerous studies performed in experimental allergic encephalomyelitis, an animal model of MS, showed that dampening the phagocytic activity of CNS-infiltrating macrophages and/or resident microglia had beneficial effects on EAE histoclinical signs (Huitinga et al., 1990; Hendriks et al., 2005; Heppner et al., 2005). These studies emphasized the role played by macrophage/microglia-derived neurotoxic molecules such as nitric oxide, reactive oxygen species and glutamate (Hendriks et al., 2005). Nevertheless, recent advances in our understanding of macrophage/microglia functions and origins have brought another level of complexity to this functional scheme. These advances are summarized in the present report, which also includes a discussion of their contribution to the current perception of macrophage/microglia activity in MS-associated neurodegeneration.
2. Recent advances in macrophage/microglia biology 2.1.
The multiple faces and origins of macrophages
Macrophages may be roughly classified into two categories: tissue-resident macrophages and inflammatory macrophages. Tissue-resident macrophages form a large family of cells that, in most cases, are ‘fixed’ within tissues. Although these cells have a number of traits in common with all macrophages (for instance, phagocytosis and antigen presentation), they also harbour tissue-specific morphological and functional features. For instance, Kupffer cells and alveolar macrophages are distinguishable by their morphology (stellate vs rounded), localization (intravascular vs intra-alveolar) and specialized activities (blood-filtering vs dust phagocytosis). Microglia are another example of macrophages with functions and morphology that are exquisitely adapted to their tissue environment (see below). All tissue-resident macrophages, with the exception of microglia, are constantly renewed by a specific subpopulation of monocytes—called ‘homoeostatic’ monocytes—that are identifiable according to surface molecules such as CX(3)CR1 (the receptor for the chemokine CX(3)CL1, also known as ‘fractalkine’) (Auffray et al., 2009). On the other hand, inflammatory macrophages—formerly known as ‘wandering’ macrophages—are activated macro-
phages that infiltrate inflamed tissues and are derived from a distinct subpopulation of monocytes, the so-called ‘inflammatory monocytes’. In contrast to homoeostatic monocytes, these precursor cells express CCR2 (the receptor for the chemokine CCL2, formerly called ‘monocyte chemoattractant protein-1’, or ‘MCP-1’), but not CX(3)CR1 (Auffray et al., 2009). In addition to inflammatory and homoeostatic monocytes, recent studies indicate that blood monocytes present with other levels of heterogeneity, most notably in their cytokine profiles. In brief, the so-called ‘type-1 monocytes’, characterized by high levels of tumour necrosis factor-alpha (TNF-a) synthesis, favour TH1-type responses, whereas the type-2 monocytes predominantly synthesize interleukin (IL)-10 and favour TH2-type responses (Strauss-Ayali et al., 2007; Weber et al., 2007; Auffray et al., 2009). Finally, monocytes are not the only category of blood cells that can generate macrophages. Other blood-circulating macrophage precursors include haematopoietic stem cells, myeloid progenitors and, possibly, granulocytes (Auffray et al., 2009).
Macrophage activation programs
Over the past decade, the idea of macrophage activation programs has emerged as a major breakthrough in the understanding of macrophage functional plasticity. Indeed, macrophages, which were until then considered to be essentially scavenger cells, were found to respond to specific activating signals by engaging in a variety of activation programs. In turn, each activation program results in the synthesis of a large array of molecules that are functionally synergistic and/or complementary (Mantovani et al., 2005). Indeed, the classical activation program, induced notably by the lymphocyte-derived cytokine interferon-gamma (IFN-g), leads to macrophage synthesis of proinflammatory molecules—in particular, TNF-a—that amplify inflammation and support the cytotoxic function of macrophages. In contrast, the so-called ‘alternative’ activation programs are triggered by molecules such as IL-4 and IL-10, and induce macrophage synthesis of anti-inflammatory molecules—in particular, transforming growth factor-beta (TGF-b) and IL10—that dampen inflammation. In addition, these alternative activation programs lead to macrophage synthesis of growth and/or neurotrophic factors that support tissue repair (Mantovani et al., 2005; Martinez et al., 2008). More important, the concept of activation programs not only applies to inflammatory macrophages, but also to tissue-resident macrophages that, once activated in inflamed tissues, are indistinguishable from inflammatory macrophages. Interestingly, macrophage activation programs are not fixed over time, and a switch from one activation state to another may occur in vivo (Arnold et al., 2007). Similarly, it is likely that M1 and M2 monocytes do not necessarily generate M1 and M2 macrophages, respectively, but are dependent upon the instruction signals delivered to macrophages within tissues (Strauss-Ayali et al., 2007).
The awakening of resting microglia
The expanding field of microglia biology has recently benefited from a number of important breakthroughs. In particular, while resting microglia were initially considered to
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be quiescent cells with no assigned functions, it has been demonstrated that, under physiological conditions, microglial cells continuously scan the CNS interstitial fluid and detect subtle alterations in its composition (Davalos et al., 2005; Nimmerjahn et al., 2005; Raivich, 2005). Such activity is supported by the unique ability of the microglial cell branches to extend, retract and explore the territory covered by each cell within minutes (Davalos et al., 2005; Nimmerjahn et al., 2005; Raivich, 2005). This means that, in terms of motility, resting microglia are, in fact, among the more active cells of the CNS. Another major finding was that a complex molecular crosstalk governs the interactions between neurons and microglia under both normal and pathological conditions. In the steadystate, CNS-resident microglia are continuously maintained in quiescent form by neuronal ‘off’ signals that include, most notably, the chemokine fractalkine, the membrane-bound molecule CD200 and neuronal electrical activity itself (Neumann et al., 1998; Biber et al., 2007). Such neuronal inhibition of microglial activation is thought to be altered under pathological conditions wherein neuronal ‘on’ signals (such as glutamate or purines) override the ‘off’ signals (Biber et al., 2007). Non-neuronal signals originating from either within or outside of the CNS may also control neuron–microglia crosstalk, and include chemokines that alter both neuronal and microglial functions (Ragozzino et al., 2006), and the toll-like receptor-4 ligand lipopolysaccharide, a component of the bacterial cell wall, known to accelerate neurodegeneration in mice after systemic administration (Cunningham et al., 2005).
monocytes (Mildner et al., 2007). In support of the latter, CD34+ myeloid progenitors were shown to target the inflamed brain and to display differentiation potential towards microglia (Davoust et al., 2006). However, it should be borne in mind that the idea of microglial renewal by bone marrow-derived cells is itself still a matter of debate. Several recent studies have questioned the use of bone marrow chimera models based on the reconstitution of lethally irradiated rodents by genetically labelled bone marrow cells. Indeed, the irradiation/ reconstitution procedure induces profound homoeostatic alterations of both resident microglial cells and the putative blood-circulating microglial precursors (Ajami et al., 2007; Mildner et al., 2007; Davoust et al., 2008). On the other hand, in humans transplanted with allogeneic bone marrow cells, donor cells were found to engraft in the host brain and to differentiate into microglia (Cogle et al., 2004). Thus, while bone marrow transplantation is clearly not a physiological model, these observations suggest that bone marrow cells may be used as vehicle cells to deliver a therapeutic molecule into the CNS (Priller et al., 2001; Asheuer et al., 2004). In support of this approach, the efficacy of allogeneic bone marrow transplantation in patients who have adrenoleucodystrophy might be due to the microglial differentiation of donor cells in the host CNS (Cartier and Aubourg, 2008).
3. New roles for macrophages/microglia in multiple sclerosis (MS)-associated neurodegeneration 3.1.
Macrophage/microglia activation programs and MS
Microglial renewal in health and disease
It has long been accepted that microglia are the only tissueresident macrophages that are not renewed by blood precursors. Indeed, microglia are originally derived from fetal myeloid progenitors that colonize the brain before the blood– brain barrier achieves full maturation (Ransohoff and Perry, 2009). It has also been shown that, in the mature CNS, microglial turnover relies on the ability of these cells to proliferate and self-renew, a functional feature that is unique to microglia among other tissue-resident macrophages (Alliot et al., 1991). However, over the past decade, numerous studies have shown that microglia may be renewed to some extent by blood-circulating cells (Davoust et al., 2008). Such renewal by bone marrow-derived cells is slow in the steady-state, but becomes considerably accelerated under pathological conditions (Priller et al., 2001). Furthermore, it has been proposed that bone marrow-derived microglia (BMDM) present with different, specific functional features compared with tissueresident microglia (Simard et al., 2006; Davoust et al., 2008). Thus, in an animal model of Alzheimer’s disease, BMDM were shown to be more efficient that resident microglia in eliminating amyloid plaques more efficiently than is usually achieved by resident microglia (Simard et al., 2006). Two types of cells are currently proposed to be these blood-circulating microglial precursors: (i) inflammatory monocytes; and (ii) myeloid progenitors. In favour of the former, the recruitment of BMDM in the inflamed brain was found to be hampered by the elimination of blood-circulating CCR2+ inflammatory
Several important results obtained in MS and its animal model, EAE, were, at least in part, drawn from the idea of macrophage activation programmes. Thus, it was shown that MS plaques comprise various subpopulations of macrophages that present with either a pro- or anti-inflammatory cytokine profile, depending on the intracytoplasmic content of myelin debris (Boven et al., 2006). Indeed, macrophages/microglia harbouring little or no myelin debris in their cytoplasm express a proinflammatory phenotype, whereas lipid-laden macrophages/microglia, preferentially located at the periphery of plaques, harbour an anti-inflammatory cytokine profile (Boven et al., 2006). In another study, a subpopulation of alternatively activated, IL-10-expressing macrophages/microglia were detected in MS plaques, again arguing for heterogeneity among the macrophage phenotypes in MS lesions (Hulshof et al., 2002). In addition, macrophages/microglia located in the normal-appearing white matter in MS brains were found to express the transducing molecule STAT4 (signal transducer and activator of transcription 4), thought to be a molecular signature of a proinflammatory (classical) activation state (Zeis et al., 2008). Taken altogether, these findings suggest that, in MS, macrophages/microglia engage different activation programs as instructed by the CNS microenvironment. Nevertheless, it should be remembered that peripheral immune signals may also instruct macrophages/microglia or their blood precursors to engage a given activation program (Cunningham et al., 2005).
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The role that may exert alternatively-activated macrophages/microglia in MS remains to be formally established. However, studies performed in the EAE model strongly suggest their involvement in tissue repair and the dampening of CNS inflammation. In EAE mice, a deficiency of intra-CNS IL-4 production prevents the development of an alternative activation programme in macrophages/microglia, leading to sustained inflammation and demyelination (Ponomarev et al., 2007). Similarly, the IL-4-induced alternative activation of microglia may lead to increased recruitment of oligodendrocytic progenitors and improvement of EAE clinical features (Butovsky et al., 2006). Furthermore, it has also been shown that macrophage precursors genetically modified to generate alternatively activated macrophages can ameliorate EAE characteristics by increasing myelin-debris clearance and creating an anti-inflammatory intra-CNS milieu (Takahashi et al., 2007). Finally, the therapeutic efficacy of glatiramer acetate has been found to rely, in part, on a shift of the monocyte cytokine profile from M1 to M2 in both MS patients and EAE mice (Kim et al., 2004; Weber et al., 2004; Weber et al., 2007).
2001). In EAE mice, it was demonstrated that CD34+ myeloid progenitors, which normally remain confined to the bone marrow compartment, are mobilized within the blood circulation and target the inflamed CNS, where they differentiate into CD34+ microglial-like cells (Davoust et al., 2006; Palazuelos et al., 2008). Such a process was found to occur during the chronic, rather than acute, phase of EAE (Vuaillat et al., 2008), thereby suggesting that microglial renewal by bone marrow cells may be triggered under conditions in which resident microglia cells are somehow overwhelmed by the extent of intra-CNS inflammation (Davoust et al., 2008). As resident microglia actively proliferate under neuroinflammatory conditions, it may be hypothesized that, when the proliferative process becomes exhausted over time, the bone marrow-derived microglia come to the rescue of the resident microglia. Unfortunately, at present, there is no experimental approach to satisfactorily and fully address this issue of microglial renewal in humans. Currently ongoing studies in MS patients are attempting to determine whether CD34+ myeloid cells and/or other cells of the myeloid population (such as inflammatory monocytes) can:
(i) present with qualitative and/or quantitative homoeostatic alterations; (ii) invade the CNS parenchyma and/or the cerebrospinal fluid; (iii) have the potential to differentiate into microglial-like cells in vitro.
Microglia/neuron cross-talk and MS
There is now increasing evidence for cross-talk between microglia and neurons in MS. In particular, neuronal expression of CD200, a molecule with inhibitory effects on perineuronal microglia, is strongly downregulated in brain gray matter in MS (Koning et al., 2007). Such a dampening of a neuronal inhibitory molecule may partially explain the extent of microglial activation observed in the cortical and deep gray matter of the MS brain (Vercellino et al., 2009). Similarly, in EAE mice, interactions between microglia and axons have been noted during the chronic phase of the disease—when T cells are virtually absent from brain parenchyma (Rasmussen et al., 2007). This further suggests that neuron-dependent signals that are not directly related to the ongoing autoimmune process are perpetuating the continuing activation of microglia in MS and EAE. The precise effects of activated microglia on neurons in MS, however, remain ill-defined. Indeed, it may be that microglia deliver a number of soluble factors that favour the proliferation/ differentiation of neuronal progenitors (Jakubs et al., 2008; Ekdahl et al., 2009). Supporting this view, a recent report found that a process of neurogenesis takes place within chronic MS plaques and that newly formed neurons interact closely with a morphologically distinct subpopulation of microglia (Chang et al., 2008). Likewise, several studies have shown that removal of myelin debris by macrophages/ microglia may facilitate remyelination, as it allows the cleared environment to emit ad hoc signals for tissue repair (Neumann et al., 2009).
Microglial renewal and MS
The issue of microglial renewal has so far been addressed in only a few studies using the EAE model. Irradiation/reconstitution experiments showed that, in EAE rats, blood-borne myeloid cells infiltrate the inflamed CNS and give rise to macrophages or to branching microglial-like cells (Flugel et al.,
Finally, it is worth bearing in mind that bone marrow microglial precursors may represent a unique cellular tool for shuttling a therapeutic gene from the blood to the brain in MS, as has been previously proposed for inherited CNS disorders (Cartier and Aubourg, 2008).
A number of studies have demonstrated that macrophages/ microglia as a whole play a crucial role in EAE pathophysiology. However, therapeutic strategies aimed at inhibiting macrophage/microglia activation appear to be difficult to design, as they may also present with considerable adverse effects. Macrophage/microglia activation programs are an opportunity to identify new therapeutic targets that allow macrophage/microglia activation to be balanced, rather than inhibited. With such an approach, it should be borne in mind that the therapeutic action of IFN-b, at least in the EAE animal model, was shown to mostly rely on an immunomodulatory effect on macrophages/microglia (Prinz et al., 2008). We expect that future effective treatments will not only induce an antiinflammatory activation state in macrophages/microglia, but will also increase their phagocytic activity towards myelin debris (Neumann et al., 2009). The evidence for macrophage/ microglia heterogeneity in terms of their origins also suggests that blocking the trafficking of specific subpopulations of macrophage/microglia blood precursors might prove to be effective in the treatment of MS. In this view, whether or not the monoclonal anti-VLA-4 antibody natalizumab specifically blocks the trafficking of one or several of these precursor
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subpopulations is a major issue to address. Finally, the potential use of microglial precursors in gene-therapy-based strategies offers new hope for the treatment of the more severe forms of progressive MS.
Acknowledgements This work was supported by a grant from Association pour la recherche sur la scle´rose en plaques (ARSEP) or Society for Research on Multiple Sclerosis).
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