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Review
Molecular triggers of neuroinflammation in mouse models of demyelinating diseases
Benoit Barrette1,*, Klaus-Armin Nave1 and Julia M. Edgar1,2
1Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann- Rein Str. 3, Goettingen, D-37075, Germany
2Applied Neurobiology Group, Institute of Infection, Immunity and Inflammation College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12-8TA, Scotland, UK
*Corresponding author
e-mail: [email protected]
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Abstract
Myelinating cells wrap axons with multilayered myelin sheaths for rapid impulse propagation. Dysfunctions of oligodendrocytes or Schwann cells are often associated with neuroinflammation, as observed in animal models of leukodystrophies and peripheral neuropathies, respectively. The neuroinflammatory response modulates the pathological changes, including demyelination and axonal injury, but also remyelination and repair. Here we discuss different immune mechanisms as well as factors released or exposed by myelinating glia in disease conditions. The spectrum of inflammatory mediators varies with different myelin disorders and has a major impact on the beneficial or detrimental role of immune cells in nervous system integrity.
Keywords: leukodystrophy; microglia/macrophages; myelin; neuroinflammation; neuropathy; T cells.
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Introduction
Myelinated axons enable rapid propagation of nerve impulses in the vertebrate nervous systems. Axonal ensheathment results from the spiral wrapping and compaction of a highly specialized glial plasma membrane. Compared to other cellular membrane, myelin is more concentrated in lipid whose composition is distinct with a higher content of cholesterol and sphingolipids (Norton and Cammer, 1984). Improved proteomic techniques resulted in the discovery of a much larger myelin proteome than originally thought, with more than 1200 myelin-associated proteins in the central nervous system (CNS) and about 500 different proteins in the peripheral nervous system (PNS) (de Monasterio-Schrader et al., 2012). Far fewer proteins, are structural components of compacted myelin, such as myelin basic protein (MBP) and proteolipid protein (PLP/DM20) in the CNS, or the peripheral myelin protein
22 (PMP22) and myelin protein zero (MPZ or P0) in the PNS. In the so-called ‘non-compacted’ myelin compartment, which may actually serve as a channel system for the maintenance of axon-glia interactions (Nave, 2010), other myelin proteins ensure transport, signaling and metabolic functions.
The more frequent inherited myelin diseases have been associated with copy number variations or mutations of genes encoding myelin structural proteins like in Pelizaeus Merzbacher disease (PMD) and Charcot Marie tooth disease (CMT). Indeed, in animal models of these diseases, overexpression and mutation of myelin membrane proteins often leads to endoplasmic reticulum stress, dysmyelination and demyelination, and axonal loss, invariably coupled to a neuroinflammatory response. Neuroinflammation comprises the activation of microglia/macrophages and astrocytes, and in more severe cases the infiltration of lymphocytes (B, T and NK cells). Microglia and the endoneurial macrophages are resident immune cells of the CNS and the PNS respectively. In their role as sentinels, they keep the neural tissue under surveillance. This is achieved by integrating numerous ligand-receptor signaling events that ultimately inform the resident microglia/macrophages about the health status of the neighboring neural parenchyma. Well studied signaling systems include the ligand/receptor pairs CD200/CD200R, CD47/SIRPα, CX3CL1/CX3CR1 and CD22/CD45 (Hanisch, 2013). Demyelination, which is often accompanied by axonopathies activates resident microglia/macrophages and, in some cases, recruits inflammatory myeloid cells (monocyte, neutrophils) and lymphocytes from the periphery. All these cells can adopt different phenotypes for specialized functions, such as phagocytic activity, cytotoxicity,
3 / 23 Bereitgestellt von | Max-Planck-Gesellschaft - WIB6417 Angemeldet | 134.76.224.212 Heruntergeladen am | 26.08.13 14:37 Secondary neuroinflammation in myelin diseases pro-inflammatory, anti-inflammatory cytokine release, and the support of tissue repair. However, their overall impact as a mixed population of immune cells on the course of disease is difficult to predict. Nevertheless, ‘neuroinflammation’ is often viewed as a response that is predominantly detrimental in myelin diseases of CNS and PNS, not only in multiples sclerosis (MS), but also in leukodystrophies and neuropathies. Indeed, immunosuppressive treatments often relieve clinical symptoms. Moreover, inflammatory cells often co-localize with sites of local demyelination and axonal injury, as studied in detail in mice that model leukodystrophies and neuropathies (Edgar et al., 2010; Ip et al., 2006b). Thus in some conditions, limiting neuroinflammation might be a promising therapeutic strategy. Notwithstanding known side effects of immunosuppressive drugs, a better understanding of inflammatory mediators in neurodegenereative diseases might help identify new targets that are advantageous compared to known immunosuppressive drugs.
Demyelination can be a cause or a consequence of neuroinflammation
In contrast to ‘dysmyelination’, which denotes a developmental perturbation of myelinating glia, the term ‘demyelination’ refers to the progressive degeneration and degradation of previously intact myelin, which can have very different causes. The best known and clinically most important is multiple sclerosis (MS), a severe neurological disease, in which demyelination is driven, if not caused, by autoreactive T cells and B cells that target oligodendrocytes and myelin antigens (Brennan et al., 2011; Derfuss et al., 2009). Another example of a consequential (secondary) demyelination caused by (primary) neuroinflammation is Guillain-Barré syndrome (GBS), in which the underlying mechanisms are less complex and better understood (Table 1). In some GBS patients, a rather sudden autoimmune response is directed against an antigenic epitope that is common to a specific ganglioside found in peripheral myelin and also in the cell wall of a gastroenteric pathogen, Campylobacter jejuni. Here, the underlying cause of demyelination, triggered by autoaggressive antibodies after an acute infection, is the ‘epitope-mimicry’ and late response against a self antigen that is shared with the foreign pathogen. It has been suspected that epitope-mimicry is also involved in multiple sclerosis (MS), although the responsible auto-antigen in MS patients is not known. The focus of this review, however, is on the opposite scenario, with demyelination and axonal degeneration being the (primary) cause of (secondary) neuroinflammation (Table 1).
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Neuroinflammation of peripheral nerves and white matter tracts is initiated when myelinating cells are lost due to apoptosis and/or necrosis and axons and myelin sheaths degenerate, e.g. after spinal cord injury and peripheral nerve lesion or after ischemic insult. Also, genetic defects that perturb oligodendrocyte or Schwann cell function, myelin architecture, or the homeostasis of axon-myelin units can be ‘sensed’ by resident immune cells that respond by becoming activated and possibily recruiting lymphocytes. In the next sections, we summarize the current knowledge of critical signaling molecules, such as DAMPs (‘damage- or danger-associated molecular pattern molecules’) and inflammatory mediators, which are exposed to immune cells in the context of demyelinating disease and that shape the overall neuroimmune response.
Oligodendroglial death and clearance of degenerating myelin membranes
Trauma or ischemia of the CNS can cause a massive loss of oligodendrocytes by apoptosis and necrosis. This is followed by a rapid influx of hematogenous inflammatory cells, i.e. neutrophils and monocytes/macrophages, to the lesion site and the activation of resident microglial cells (David and Kroner, 2011). It is still unresolved whether these cells are ultimately beneficial for CNS integrity or whether they cause a second wave of tissue damage due to their high phagocytic activity. In vitro studies have shed light on the molecular machinery orchestrating the disposal of myelin debris when oligodendrocytes die by apoptosis or necrosis. An important mechanism is the activation of the complement system with proteins that bind myelin debris and promote phagocytosis by microglia/macrophages via the complement receptor CR3/MAC-1 (Bruck and Friede, 1991; Reichert and Rotshenker, 2003). By studying microglial cultures to which exogenous myelin vesicle were added and in which CR3/MAC-1-blocking antibodies and complement were present, it was shown that about 80% of the myelin clearance depends on CR3/MAC-1 signaling. The remaining CR3/MAC-1-independent myelin phagocytosis could be attributed, at least in part, to the scavenger receptors AI/II (SRA-I/II), which have a high affinity for oxidized lipids (Reichert and Rotshenker, 2003). Also after sciatic nerve injury in the PNS, CR3/MAC-1 and SRA-I/II are the dominant receptors on macrophages responsible for the first phase of rapid myelin debris clearance that occurs within 6 days after crush. Here, the late phase of myelin clearance was shown to be more dependent on the binding of myelin-specific IgG and IgM
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Cuprizone-induced demyelination constitutes an animal model in which the acute loss of oligodendrocytes by apoptosis is triggered in only a few vulnerable myelinated tracts, primarily the corpus callosum. It is achieved by feeding adult C57bl/6 mice for about 2.5 weeks with a diet containing 0.2% cuprizone, a toxic copper chelator, which produces a loss of subcortical white matter that overlaps with robust microgliosis as a sign of myelin clearance (Voss et al., 2012). Release by dying oligodendrocytes of cytosolic DAMPs, which are ligands for Toll-like receptors or purinergic P2X receptors (DNA, RNA, heat shock proteins, ATP) (Pineau and Lacroix, 2009), are likely to be detected by microglia/macrophages and astrocytes. Indeed, it was recently reported that myelin stripping in the corpus callosum of mice fed with curprizone is stalled when proliferating (reactive) astrocytes were specifically killed by transgenic toxin expression (Skripuletz et al., 2012). This could indicate that astrogliosis is essential for microglial phagocytosis (Figure 1). In fact, expression of CXCL10 (a key pro-inflammatory chemokine in astrocytes, which serves to recruit inflammatory microglia/macrophages) was lower in mice in which astrogliosis was prevented. This model is supported by the observation that administration of laquinimod (an immunomodulatory drug interfering with the pro-inflammatory NF-κB pathway in astrocytes) in cuprizone fed mice decreases the release of CXCL10 and other cytokines, and also the extent of axon loss and demyelination (Bruck et al., 2012).
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Detection of abnormal oligodendrocytes, stripping of compact myelin and clearance of myelin debris could also be initiated by microglia/macrophages upon recognition of an ‘eat-me’ signal. A well-known example is phosphatidylserine (PS) when translocated to the outer leaflet of a plama membrane and binding the soluble Gas6 protein (for ‘growth arrest-specific gene 6’) (Figure 1). The resulting PS-Gas6 cluster is a ligand for a triad of protein-tyrosine kinase receptors, termed TAM-receptors (Tyro3, Axl, Mer), which are expressed on microglia/macrophages and trigger phagocytosis (Binder and Kilpatrick, 2009). Genetically inactivating the Axl receptor, a protein upregulated on microglia during cuprizone treatment, prevents microgliosis and delays the generation of myelin debris and its clearance in mutant mice (Hoehn et al., 2008). Furthermore, the spontaneous remyelination following the switch to normal chow is slightly delayed when Axl is absent, and there is a significant increase of autophagosome-like vesicles in dystrophic axons. Some of these histopathological defects, when appearing in wild-type mice treated with cuprizone, can be diminished by infusion of recombinant Gas6 (rhGas6) directly into the brain, which promotes the clearance of myelin debris (Tsiperson et al., 2010). In cuprizone fed mice, the receptor TREM-2b ('triggering receptor expressed on myeloid cells-2b') is the most abundant phagocytosis receptor on microglia cells, however its myelin-associated physiological ligand remains unknown (Voss et al., 2012). It is tempting to speculate that targeting these molecules opens a possibility to accelerate phagocytosis in diseases in which protracted myelin clearance is a burden on axon survival (Figure 1).
The molecular machinery underlying phagocytosis of myelin debris by microglia/macrophages has been studied in vitro and in cuprizone-fed mice. However, validation of these mechanisms in other in vivo models with demyelination is important to understand the role of neuroinflammation, a known bystander effect of inherited myelin diseases. This could be done in mouse models of human myelin diseases, such as Plp1 overexpressing (for PMD) or MPZ heterozygous mice (for CMT1B) that reveal a substantial degree of secondary inflammatory response (Ip et al., 2006a,b).
Leukodystrophies and neuropathies caused by perturbed expression of myelin protein genes
A unique cause of inherited myelin diseases is the duplication of genes that encode polytopic myelin membrane proteins. For instance, duplication of the X chromosome-linked proteolipid
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Duplication of peripheral myelin protein 22 (PMP22) gene underlies the most frequent form (about 60%) of inherited demyelinating neuropathy, Charcot-Marie Tooth disease type 1A (CMT1A). CMT1A patients develop distally pronounced sensory loss and progressive muscle weaknesses, leading to loss of tendon reflexes and foot deformities (Wrabetz et al., 2004). While consequences of the neuroinflammatory response on the progression of pathologies have not yet been systematically investigated in human PMD and CMT1A patients, corresponding rodent models of these diseases have demonstrated an important effect of microglia/macrophages and lymphocytes in disease expression.
Duplications of the X-linked PLP1 gene have been modeled in transgenic mice carrying autosomal Plp1 transgenes (Readhead et al, 1994). Two mouse lines (Plp66/66 and Plp72/72), with 7 and 3 copies of a Plp1 cosmid per haploid genome, have been most widely studied. The mouse line Plp72/72, which overexpress Plp1 about 1.6-fold, are bona fide PMD models with ataxia, tremors, and seizures. In all transgenics the degree of dysmyelination/demyelination is proportional to Plp1 gene dosage (Readhead et al., 1994). In the CNS of 12 months-old Plp66/+ mice, corpus callosum, cerebellum, spinal cord, and optic nerves are filled with numerous (CD11b+) leukocytes (Ip et al., 2006a). Moreover, CD11b+ and CD45+ inflammatory cells are detected in the optic nerve where active demyelination is associated with axonopathy (Edgar et al., 2010; Ip et al., 2006a). These PMD models have enabled the identification of inflammatory cells receptors and cytokines relevant for the pathology progression. For example, in Plp66/+ mice, Ip et al. demonstrated that ablation of the gene for sialoadhesin (Sn/CD169), a macrophage-restricted adhesion molecule and receptor for sialylated glycolipids, tempers the secondary neuroinflammation as well as the extent of demyelination and axonal degeneration in the optic nerve (Ip et al., 2007). A similar modulatory function can be seen in the peripheral nervous system. Here, MPZ is the most abundant membrane protein of myelin synthesized by Schwann cells. Mpz heterozygous mice develop a late onset neuropathy with secondary infiltration of macrophages and active demyelination, beginning at 4 months of age. When these mutants (which model CMT1B) additionally lack expression of Sn/CD169 in macrophages, the demyelinating histopathology is significantly attenuated (Kobsar et al., 2006).
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Apparently, Sn/CD169 and its myelin-associated ligands (i.e. sialated glycolipids) constitute a signaling pathway common to CNS and PNS that controls myelin phagocytosis. For heterozygous Mpz mice, it has been shown that cytokine-like macrophage-colony stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1) are released by mutant Schwann cells, which are then instrumental in stimulating the proliferation and recruitment, respectively, of resident macrophages. Lowering the release of these cytokines substantially reduces the extent of PNS demyelination (Martini et al., 2008) (Figure 2).
The normal localization of CNS microglia or PNS macrophages in myelinated nervous tracts allows these cells to be the first to respond to myelin-derived ‘eat-me’ signals and to initiate myelin fragmentation and later the clearance of myelin debris. Interestingly, the pathological demyelination observed in these PMD and CMT1B models is enhanced by the adaptive immune system, i.e. secondarily invading lymphocytes. This was experimentally shown by crossbreeding either Plp66/+ transgenic or Mpz heterozygous mice with recombinase RAG-1 deficient mice, which lack functional B and T cells. This led in both lines to a reduction in the degree of demyelination in the optic and peripheral nerves, and allowed more axons to survive (Ip et al., 2006a; 2006b). It is therefore surprising that a similar lack of B and T cells did not affect peripheral demyelination in a Pmp22 transgenic mouse model of CMT1A (Kohl et al., 2010). We hypothesize that the secondary immune response differs between mouse models as a function of the underlying myelin defect. In Mpz heterozygous mice, a relative lack of the major adhesion protein of myelin is likely to result in local delamination (Martini et al., 1995), as shown in detail for a cholesterol-deficient mutant with a similar reduction of MPZ in myelin (Saher et al., 2009). Unstable myelin may lead to membrane shedding, phagocytosis and antigen presentation to autoimmune T cells, all of which might not be a feature of Pmp22 transgenic mice. We also note that Mpz heterozygous mice harbor T cells that can be stimulated by MBP (Schmid et al., 2000), suggestive of prior epitope spreading.
CD8+ T cells constitute the most abundant lymphocyte population in the brains of Plp1 transgenic mice (line Plp66/+) and are clonally expanded in some animals (Leder et al., 2007). The presence of CD8+ cells raises the question whether they participate directly in CNS demyelination by inducing oligodendrocytes apoptosis by T cell-mediated cytotoxicity. CD8+ cells invading the optic nerve have a preferential localization at the paranodal/juxtaparanodal region, a likely bottle neck for retrograde axonal transport (Ip et al., 2012). The antigen specificity of these CD8+ cells from mutant brains is unknown,
9 / 23 Bereitgestellt von | Max-Planck-Gesellschaft - WIB6417 Angemeldet | 134.76.224.212 Heruntergeladen am | 26.08.13 14:37 Secondary neuroinflammation in myelin diseases and splenocytes from these mice do not proliferate in response to predicted MHC-I peptides synthesized in vitro (Leder et al., 2007). It is still unclear how lymphocytes in the lymphoid organs are stimulated when oligodendrocytes are dysfunctional, and how they reach the CNS. It is possible that a small number of autoreactive T-cells recruits a second wave of lymphocytes through a perturbed blood brain barrier. That could be tested by cross-breeding Plp1 transgenic with CCR6-deficient mice, in which the primary access of autoimmune T cells to the brain via the choroid plexus is blocked (Reboldi et al., 2009). Similarly, cross-breeding Plp1 transgenics with β2m KO mice (in which the lack of β2-microglobulin prevents the assembly of functional MHC class I) could help decide whether it is MHC class I-dependant mechanisms of infiltrating CD8+ cells (Linker et al., 2005) that contribute to demyelination and axonopathy in this model.
Surprisingly, massive killing of transgenic oligodendrocytes with diphtheria toxin causes widespread demyelination and microglia/macrophage activation, but is not sufficient to attract a significant number of T cells (Locatelli et al., 2012; Pohl et al., 2011; Traka et al., 2010). Also in others models of induced oligodendroglial apoptosis (i.e. cuprizone), the recruitment of T cell is marginal. This contrasts with the phenotype of previously described mutants, in which various genetic perturbations of oligodendrocyte function (Plp1 transgenic, Pex5 conditional-KO mice, see below) causes significant lymphocyte invasion concomitant with demyelination and low level of oligodendroglial apoptosis. This suggest that it requires live (but injured) oligodendrocytes to trigger T cell infiltration. Alternatively, there are underlying signals from degenerating neurons and axons that cause T cell infiltration, which are therefore due to secondary axonal loss in myelin mutant mice. Among different models, the variability of axonal involvement differs and perturbations of myelin function (in Plp1 trangenic mice) may be more detrimental to axon survival than transient demyelination induced by diphtheria toxin (Locatelli et al., 2012; Pohl et al., 2011; Traka et al., 2010). We note that, in contrast to oligodendrocytes, the genetic ablation of adult hippocampal neurons in transgenic mice with an inducible diphteria toxin gene causes significant infiltration of T cells (Agarwal et al., 2012).
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Neuroinflammation of white matter in mouse models of peroxisomal and lipid storage disorders
Demyelinating disease can occur as a result of dysfunction of organelles, such as peroxisomes and lysosomes, which play a major role in lipid metabolism of myelinating cells. Lipids make up 70-75% of the dry weight of purified myelin membranes. Some of these lipids and their derivatives are viewed as potential stimulators of immune responses in leukodystrophies characterized by an abnormal myelin lipid turnover. For example, the X-linked recessive adrenoleukodystrophy (X-ALD) is a demyelinating disorder caused by a peroxisomal dysfunction, and has an incidence of 1 in 21 000 male newborns (Bezman et al., 2001). In these patients, the ABCD1 gene, which encodes a membraneous transporter that shuttles very long chain fatty acids (VLCFA) into the peroxisomal lumen for their degradation by β-oxidation, is mutated. In severe cases, male patients are affected at childhood by the cerebral form of X-ALD, which produces a rapid progressive demyelination of subcortical white matter (Moser et al., 2007). Functional deficits in this disease, starting between 4 and 8 years of age, are then caused by focal myelin loss, axonal degeneration, and recruitment of inflammatory cells to demyelinated areas, typically in the periventricular white matter of the parieto-occipital cortex (Eichler and Van Haren, 2007).
In patients with metachromatic leukodystrophy (MLD), the lysosomal degradation of sulfatide is impaired due to mutation of the arylsulfatase A gene (Asa1). Sulfatide (the sulfated form of galactocerebroside) is a frequent lipid of the myelin sheath but accumulates also in other neural cells. MLD has an incidence 1 in 40 000 births and manifests with ataxia and hypotonia, whereas its onset can vary widely between childhood to adulthood. With increasing age, there is deterioration of hearing, vision, speech and cognitive capabilities, and also peripheral nerves become involved. With respect to neuroinflammation, activated perivascular microglia/macrophages are a salient feature of demyelinated lesions in MLD (Eichler and Van Haren, 2007). Progression of disease in X-ALD (or MLD) can be halted when allogeneic hematopoietic cell transplantation or autologous hematopoietic stem cell gene therapy are performed before the appearance of severe neurologic deficits (Biffi et al., 2011; Cartier et al., 2009). The benefit of this therapy has been accredited to the invasion of donor-derived microglia/macrophages that have normal peroxisomal (and lysosomal) functions.
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So far, mutations in Abcd1 and Asa1 genes in mice have failed to provide clinical models of X-ALD and MLD diseases. To obtain a phenocopy of X-ALD in mice, including CNS demyelination and the secondary inflammatory response, a new model has been created by targeting the gene for the peroxisomal biogenesis factor peroxin-5 (Pex5) selectively in oligodendrocytes (Pex5flox/flox*CNP-Cre/+ mice), causing the loss of virtually all oligodendroglial peroxisomal functions (Kassmann et al., 2007). This mouse is viable and is well myelinated until the sixth month of life when hindlimb ataxia becomes obvious. With further ageing, clinical dysfunctions worsen (hunchback, hindlimb paresis, tremor, paralysis) and culminate in terminal breathing difficulties at about one year. Magnetic resonance imaging revealed that sub-cortical myelinated fiber tracts are the first to deteriorate (corpus callosum, hippocampal fimbria, anterior commissure) with minimal impact in the caudal brain. Elevated VLCFA concentration in the brain and locomotor dysfunctions correlate with neuroinflammation, which is dominated by activated microglia/macrophages and infiltrating CD8+ T-cells into areas of demyelination and axonal loss. This model will allow us to determine the cause of neuroinflammation, the property of infiltrating B and T cells and to genetically uncouple inflammation and demyelination. Essentially the same phenotype is seen in Nestin-Cre*Pex5 mutant mice that lack peroxisomes from virtually all neurons and macroglial cells (Bottelbergs et al., 2012). This suggests that the key anti-inflammatory function in the brain is provided by oligodendroglial peroxisomes, which are also associated with the myelin sheath (Kassmann et al., 2011).
Why secondary neuroinflammation is stronger in this compared to other mouse models of human leukodystrophies is unknown. It is possible that a pro-inflammatory milieu is caused by the accumulation of eicosanoids (prostaglandins and leukotrienes) that are normally degraded by peroxisomal β-oxidation (Kassmann and Nave, 2008). However, the specific blockage of only peroxisomal β-oxidation in oligodendrocytes (Cnp1-Cre*Mfp2flox/flox) does not cause an equivalent degree of inflammatory demyelination (Verheijden et al., 2013). Another peroxisomal mutant (Gnpat-/-) that completely lacks the ability to synthesize ether lipids (plasmalogens), suggests that loss of this radical scavenger is not sufficient to trigger inflammation.
Bottelbergs et al. have found, in Nestin-Cre*Pex5flox/flox mouse, a strong upregulation of both complement factor C1q and TNF-α in the corpus collosum prior to any sign of inflammatory demyelination (Bottelbergs et al., 2012). The soluble C1q protein is part of the complement system. When C1q binds cellular membranes, a cascade of reactions with the activation of
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To experimentally study abnormal sulfatide storage in the brain, a mild clinical model of MLD was created in mice by combining the genetic targeting of the Asa1 gene with sulfatide overproduction in a line of PLP-Gal3st1 transgenics (Ramakrishnan et al., 2007). These mice show a clasping reflex of their hindlimbs at about 16 months of age and develop paralysis later. Abnormal (alcianophilic) lipid inclusion bodies were detected in microglia/macrophages of the spinal cord white matter, and in optic nerve and corpus callosum of affected mice. It is unknown what induces macrophages to engulf sulfatide-enriched myelin. Sulfatides and gangliosides induce the release of a plethora of pro-inflammatory mediators from cultured primary microglia; a response that can be blunted by pretreating these cells with small interfering RNA against L-selectin (CD62L) or a TLR4 antagonist, respectively
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(Jeon et al., 2008; Jou et al., 2006). These receptors could provide new targets for the development of therapeutic strategies (Figure 2).
Conclusions
Despite the fact that the CNS and the PNS are considered ‘immune privileged’ tissues with respect to the blood-brain and blood-nerve barriers’ restricted permeability, the nervous tissue is constantly kept under surveillance by infiltrating lymphocytes and resident microglia/macrophages. This is of vital importance because neural cells are host to infectious agents, and these are readily reactivated when immune surveillance fails. In addition to this defensive role, immune cells also fulfill housekeeping tasks such as in synapse remodeling and myelin turnover. In the white matter, inherited myelin defects are often associated with the abnormal activation of microglia/macrophages and occasionally a significant infiltration of clonally expanded lymphocytes (CD4+, CD8+ T cells). Studied in mouse models of PMD, adrenoleukodystrophy, myelin-associated lipid storage diseases (MLD), and various peripheral neuropathies (Charco-Marie-Tooth disease), these immune cells are observed in close proximity to sites of pathology (demyelination, axonopathy) and have been shown in some models to contribute to disease severity. In other models, however, such as in toxic myelin injury (cuprizone) and brain trauma (or nerve injury), immune cells contribute to a more efficient clearance of debris and thus improved remyelination and regeneration. Clinical applications of these observations will be possible only when independent assessments of the extent of neuroinflammation in the corresponding human leukodystrophies and peripheral neuropathies will be conducted, given the many differences of the immune responses emerging between mouse and human (Seok et al., 2013). Therefore, the outcome of a neuroinflammatory response is context specific. The specificity is determined by the ligands that glial cells present to resident cells of the immune system. Harnessing glial mediators for a supportive (rather than detrimental) immune response would be of a great benefit for leukodystrophy and neuropathy patients. This requires a better understanding of the complex array of neuroimmune activators that appears specific for each disease.
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Acknowledgments
We thank Rudolf Martini for many helpful discussions and Dr. Stefan Nessler for comments on the manuscript. B.B. was supported by a postdoctoral fellowship from the Multiple Sclerosis Society of Canada and the Deutsche Forschungsgemeinschaft (SFB/TR43). J.M.E. was supported by an ERC Advanced Grant to K.A.N.
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Tables and figures
Table 1 Cause of demyelination associated with inflammation in human disorders affecting the nervous system.
Cause of demyelination Examples of human disorders Rodent models - Multiple sclerosis (MS) - Experimental - Guillain-Barré syndrome autoimmune (GBS) Autoimmunity, including epitope mimicry encephalomyelitis (EAE) - Chronic inflammatory and abnormal immune regulation - Experimental demyelinating autoimmune neuritis polyradiculoneuropathy (EAN) (CIDP) - Stab wound lesion Contusion injury - Toxic injury (Cuprizone, - Brain and spinal cord injury Ethidium Bromide, Oligodendrocyte and Schwann cell death, - Ischemia Lysolecithin) caused by trauma, viral infection, apoptosis, - Progressive multifocal - Middle cerebral artery necrosis leukoencephalopathy (PML) occlusion (MCAO) - Nerve injury - Theiler’s virus Mouse hepatitis virus - Sciatic nerve crush - Pelizaeus-Merzbacher disease (PMD) Genetic defects of oligodendrocytes and - Charcot-Marie Tooth - Corresponding mouse Schwann cells, including myelin gene disease (CMT) mutants: spontaneous or duplications, point mutations, lipid storage - Adrenoleukodystrophy (X- generated by gene disorders ALD) targeting* - Metachromatic leukodystrophy (MLD) *For details see text
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Figure 1 Microglial activation and degenerating myelin disposal following cuprizone mediated oligodendroglial apoptosis. Dietry cuprizone induces the death of oligodendrocytes and cause compact myelin damage in addition to axonal transport blockage (spheroids). Apoptosis induces the translocaton of phosphatidylserine (PS) to the cell surface where it can bind Gas6. Meanwhile, heat-shock proteins (HSP) and adenosine triphosphate (ATP) released from dying oligodendrocytes, which are ligands of astrocytic Toll-like receptor (TLR) and purinergic 2X receptors (P2X), respectively, trigger the release of CXCL10. CXCL10 primes the microglia to start their myelin phagocytosis program. This occurs through Axl receptors which recognizes Gas6 and potentially by other receptors (Trem2b, CR3, SRA I/II).
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Figure 2 Hypothetical molecular neuroimmune activation model in PMD/CMT and peroxisomal biogenesis/MLD diseases. A vicious cycle of demyelination is initiated and maintained by a primary myelinating cell defect, that subsequently activates microglia/macrophages and T cells. In PMD/CMT models (right part), aberrant myelin protein expression (PLP, MPZ) modifies the composition of lipid rafts and the exposure of the ganglioside sialic acid moiety (red triangle). These molecules react with the microglial sialoadhesin (Sn/CD169) receptor which mediate the myelin engulfment. Perturbed Schwann cells would reinforce these activation processes by MCP-1 (dark blue asterisks) release, which binds its receptor (CCR2) on resident macrophages. T cells could perpetrate a second hit on defective myelin, promoting demyelination and secondary axonal injury. When peroxisome biogenesis is impaired (left part), altered myelin sheaths (light blue rectangles) owing to accumulation of VLCFA, are tagged by C1q molecules which act as ‘eat-me’ signals to trigger the microglial myelin debris (light blue half moon) detachment and phagocytosis via CR3 which can be supported by eicosanoides (e.g: leukotriene, dark blue asterisks acting on its receptor LTR). This leads also to the recruitment of T cells whose functions are not clear. In MLD, other lipophilic receptors (TLR, CD62L) can contribute to the same activation process.
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