Immune Cure

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Perspective Taking Advantage of the Systemic Immune System to Cure Brain Diseases V. Wee Yong1,* and Serge Rivest2,* 1Hotchkiss Brain Institute and the Departments of Clinical Neurosciences and Oncology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada 2Laboratory of Endocrinology and Genomics, CHUL Research Center and Department of Molecular Medicine, Laval University, 2705 Laurier boul., Que´bec G1V 4G2, Canada *Correspondence: [email protected] (V.W.Y.), [email protected] (S.R.) DOI 10.1016/j.neuron.2009.09.035

The systemic immune system has the ability to modulate multiple brain functions, including autonomic responses, glial reactivity following neural injuries, and neuronal excitability. Immune stimuli also influence microglia subpopulations originating from blood progenitors, and neuroprotective and reparative capacities of blood-derived microglia were recently described in mouse models of spinal cord injury and brain disorders. Furthermore, reparative roles for various immune subsets have been recognized, such as in inducing myelin repair. Nonetheless, uncontrolled and excessive activation of immune responses can be detrimental. The development of strategies to stimulate the systemic immune system safely to protect or repair brain disorders remains a major challenge ahead, but important inroads have been made. We discuss here some of the mechanisms underlying the neuroprotective and reparative effects of the systemic immune system and the most promising immunotherapies tested in mouse models of injuries and diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Introduction Inflammation is a general term for reactions occurring after most kinds of tissue injuries or infections or immunologic stimulations as a host defense against foreign or altered endogenous substances and to regain homeostasis or enable repair. The local inflammatory reaction is characterized by an initial increase of blood flow to the site of injury, enhanced vascular permeability, and selective accumulation of different effector cells from the peripheral blood to injured regions. These cells, mostly circulating neutrophils and monocytes and local resident macrophages, together mount rapidly an inflammatory response that is characterized, among other features, by cytokine production. Their secretion into the bloodstream is a key step for triggering the neuronal activity and subsequent neurophysiological responses that take place during systemic and localized tissue insults. Cytokines influence many neuroendocrine systems, the most prominent of which is the activation of the hypothalamicpituitary adrenal (HPA) axis, resulting in the release of ACTH and glucocorticoids. These steroids are the most powerful negative feedbacks on innate immune cells. Other autonomic functions (e.g., fever, sickness behavior) are also dependent on bilateral communications between the immune system and brain. Circulating monocytes are also involved in the brain’s reaction to systemic immune stimuli (D’Mello et al., 2009). Indeed, D’Mello et al. recently found that peripheral TNFa signaling stimulates monocyte chemoattractant protein (MCP)-1/CCL2 production in microglia, which drives the subsequent infiltration of CCR2-expressing monocytes into the brain. These events contribute significantly to the development of hepatic inflammation-associated sickness behavior (D’Mello et al., 2009). Thus, immune cells can infiltrate the CNS in the presence of systemic inflammation and modulate neural activities. Such a

phenomenon was known to occur in brain diseases, the best example being multiple sclerosis (MS), where immune dysfunction is robust and therapies are needed to reduce the prominent entry of immune cells into the CNS. On the other hand, particularly in conditions where systemic immune dysfunction is not as widespread as that occurring in MS, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), strategies have been proposed to stimulate immune cells to improve neural outcomes. While somewhat complicated, as inflammatory activation in these diseases can lead to both beneficial and detrimental effects (see Lucin and Wyss-Coray [2009] in this issue of Neuron and Rivest [2009]), this review will focus specifically on how one might take advantage of the systemic immune system to treat brain diseases safely. Immune Cells with a Systemic Origin Despite having the same origin, circulating monocytes and tissue macrophages, including microglia (Figure 1), encompass a wide range of phenotypically and functionally distinct subpopulations (Soulet and Rivest, 2008). Recently, a spectrum of activation has been elaborated for macrophages, consisting of two main subgroups: inflammatory macrophages (M1) and alternatively activated macrophages (M2a, -b, or -c). Each subgroup is characterized by a distinct profile of gene expression, and accordingly, each mediates and modulates different functions (Nahrendorf et al., 2007). In this respect, M1 macrophages express TNFa and iNOS and have important proteolytic activity, while M2 macrophages possess important immunomodulatory and tissue repair and remodeling properties (Martinez et al., 2009). Similarly, two different populations of circulating monocytes have been identified based on the expression pattern of specific surface molecules (Auffray et al., 2009). In mice, the

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Perspective Figure 1. Microglial Cells Microglia are the resident immune cells of the brain, and they are constantly patrolling the cerebral microenvironment. As depicted by panel (A), they are present in the entire central nervous system (CNS), including the spinal cord. There are regions that are more populated than others, and the white matter generally contains less microglia than the grey matter. They are highly ramified cells, and their processes are very active and plastic even during nonpathological conditions. Although their exact origin still remains to be fully established, both macrophages and microglial cells derive from myeloid progenitors. There are subpopulations of microglial cells, each of which may have different origins, i.e., the primitive macrophages from the yolk sac and those newly differentiated from monocytes or their progenitors. Concrete evidence demonstrating the capacity of bone marrow stem cells (BMSCs) to populate the CNS and differentiate into microglial cells was obtained in chimeric mice transplanted with bone marrow cells expressing green fluorescent protein (GFP). With the use of this model, many researchers have found donor-derived cells in the brain of host animals, and BMSCs indeed have the ability to populate the CNS and differentiate into functional parenchymal microglia as well as perivascular microglia (C and E). It is important to mention that the origin and role of microglia in the adult brain still remain highly debated today. (A and G) Resting microglia (green cells, immunofluorescence using a primary antibody directed against iba1; blue nuclei, DAPI). (B, D, and F) Highly ramified microglia (red cell, immunofluorescence using a primary antibody directed against iba1). (C and E) Bone-marrow-derived microglia from chimeric mice transplanted with bone marrow stem cells expressing green fluorescent protein (green GFP cells). The confocal images of the microglia subtypes were taken by Paul Pre´fontaine.

relative expression levels of chemokine receptors CCR2 and CX3CR1 (e.g., CCR2high/CX3CR1low; CCR2low/CX3CR1high) define two subpopulations of monocytic cells, and interestingly, each correlates with the presence of Gr1 and/or Ly-6C surface antigen (Auffray et al., 2009). Therefore, CCR2+/Gr1+/Ly-6Chigh defines inflammatory monocytes, while CX3CR1+/Gr1 /Ly6Clow refers to blood-vessel-patrolling monocytes. However, monocyte biology is becoming increasingly complex and may be tissue dependent—an increasing number of cluster of differentiation (CD) molecules are being validated to complement other markers to ascertain exact subpopulations of monocytes more specifically. As such, a third subset of the monocyte population (e.g., CD3 CD19 NK1.1 Ter119 SSCloCD11bhiCD62L+ Gr1int) may encompass the population of circulating precursors of microglia (Soulet and Rivest, 2008). Although the differentiation of monocytes into macrophages is not very well understood, it appears that in a tissue under pathological conditions, newly recruited CCR2+ monocytes give rise to M1-activated macrophages, while CX3CR1+ monocytes adopt a more M2-like profile (Nahrendorf et al., 2007). The recruitment of each monocytic population is time dependent, correlating with the different phases of the tissue insult and repair. In vitro data corroborate these observations, as proinflammatory ligands like LPS or IFNg favor macrophage differentiation toward an M1 profile,

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while IL-4, IL-13, IL-10, and TGFb shift the development of monocytes into a M2 phenotype. Much of these observations are derived from studies on peripheral organs, and little is known regarding whether such classification also exists for microglia and how important different subsets are to brain functions, injury, and diseases. There is a massive infiltration of bone-marrow-derived microglia (BMDM) during experimental models of stroke and most mouse models of neuronal injury (Soulet and Rivest, 2008). Although BBB disruption facilitates this recruitment, BMDM are also found in models where the BBB is not compromised (e.g., in the hypoglossal nucleus after lesion of its innervating nerve). Data from Schwartz and colleagues have shown that the spatial organization of the infiltrating myeloid progenitor cells around the lesion site has a direct impact on functional indices of recovery following spinal cord injury; in another study, this group has elegantly shown that infiltrating monocyte-derived cells mediate a function essential for repair that cannot be provided by resident microglia during spinal cord injury (Shechter et al., 2009). Spatial organization and subpopulation of microglia/macrophages originating from blood precursors can therefore have a direct influence on the repair process occurring after injury of the CNS. It is interesting to note that the activity of these innate immune cells can be modulated by cells of the adaptive immune system.

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Perspective Damaged Neuron

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Blood Compounds that activate or enhance cell recruitment and innate immunity (M-CSF, TLR ligands, adjuvants, lifestyle, ...)

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Figure 2. Systemic Immune Approaches to Clear Amyloid Beta in Alzheimer’s Disease Activation of the systemic innate immune system and bone marrow cells may be a powerful approach to treat AD and eliminate Ab from the CNS. This can be done by specific toll-like receptor (TLR) ligands and other adjuvants, M-CSF, and immunization against Ab. Other immunotherapies that have been tested in mouse models of AD include a T cell-based vaccination with glatiramer acetate, a drug used in multiple sclerosis. Finally, the genetic engineering of bone marrow stem cells to upregulate genes encoding chemokine receptors (e.g., CCR2), TLRs, CD14, Ab-degradating enzymes, and neurotrophic factors may be a new direction to improve recruitment and functionality of bone-marrow-derived microglia/macrophages (BMDMs) in the CNS and favor their polarization toward neuroprotection. Such systemic immunotherapies may also be applied to other CNS diseases, because toxic and extracellular proteins are becoming a common feature of many brain disorders.

Immunization against amyloid-β (active and passive)

factor (M-CSF) levels were found in patients with presymptomatic AD or mild cognitive impairment (MCI), which together with low levels of other hematoEnhanced expression of: poietic cytokines predicted the rapid evo+ TLRs (2, 4, 9) and CD14 lution of the disease toward a dementia + Scavanger Receptors + Trophic factors state 2–6 years later (Ray et al., 2007). + Amyloid-β degradating enzymes Systemic M-CSF administration is a + Enzymes that activate pro-drugs Viral transduction powerful treatment to stimulate bone+ Chemoattractants (CCR2, ...) marrow-derived microglia, degrade Ab, and prevent or improve the cognitive decline associated with Ab burden in Indeed, regulatory T cells have the ability to modulate microglial a mouse model of AD (Boissonneault et al., 2009). The mobilizareactivity to injury and play a key cerebroprotective role in acute tion of precursor cells in the bone marrow together with the effects of the cytokine on Ab degradation by microglia (Majumexperimental stroke (Liesz et al., 2009). dar et al., 2007) are mechanisms underlying the great potential of this systemic immune approach. Systemic Immune Therapies in Alzheimer’s Disease The recent papers by Ajami et al. (2007) and Mildner et al. Many studies have provided evidence that microglial cells are attracted to amyloid deposits both in human samples and in (2007) raised concerns regarding the ability of circulating rodent transgenic models that develop Alzheimer’s disease (AD) progenitors to enter and differentiate into functional microglia. (for a review, please see Simard et al. [2006]). We recently found Their work suggests that such a phenomenon is a consequence numerous BMDM closely associated with amyloid plaques, and of the generation of chimeric mice using either BMSC transplanthey serve to slow the progression of the disease by removing tation or irradiation. Technical details of chimeric models have amyloid beta (Ab) from the CNS (Simard et al., 2006). Upregulat- been discussed in a previous review (please see Soulet and Riving TLR2 gene expression in bone marrow cells restores the est [2008]). It is important to mention that beneficial effects of cognitive decline of the APP/PS1 mice in the context of TLR2 BMDM in AD are not only reported in chimeric mice using the gene deficiency (Richard et al., 2008), and blocking TGF-b- irradiation technique, but also in nonirradiated mice. Moreover, Smad2/3 innate immune signaling in bone-marrow-derived cells APP mice that have their hematopoietic system reconstituted improved AD-like pathology (Town et al., 2008). Brain paren- from WT mice always perform significantly better (e.g., less rapid chymal and cerebrovascular Ab deposits and Ab abundance cognitive decline) than intact APP or chimeric APP mice transwere markedly (up to 90%) attenuated in Tg2576-CD11c-DNR planted with bone marrow stem cells taken from APP mice (M. mice (Town et al., 2008). This was associated with increased infil- Filali and S.R., unpublished data). Overall, converging informatration of Ab-containing peripheral macrophages around cere- tion emphasizes that competent immune cells are highly beneficial to clear toxic Ab; the challenge is to define the mechanisms bral vessels and Ab plaques. Consequently, stimulating the hematopoietic system may be that will allow them to be more effectively recruited where they considered as a new therapeutic approach for treating AD are absolutely needed, and without incurring the harmful effects (Figure 2). In this regard, low macrophage colony-stimulating of an overly stimulated immune system. Bone Marrow Transplantation

Bone Marrow Stem Cells (BMSCs)

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Perspective Other systemic immune therapies (e.g., active immunizations against Ab1-42) in mouse models of AD were previously found to remove Ab from the CNS, which ultimately improves the cognitive decline associated with the amyloid cascade. These data largely justified the first clinical trial with active immunization in patients with mild to moderate cognitive impairment. Although the clinical trial was stopped due to the meningo encephalitis that developed in 6% of patients, the treatment seemed quite effective to clear the senile plaques. Postmortem analysis of a limited number of brains also revealed strong microglial reactivity to Ab and infiltration of T cells. Other approaches to boost immune functions have also been efficacious in animal models of AD. Nasal vaccination with a synthetic copolymer used to treat MS potently decreases senile plaques in a mouse model of AD (Frenkel et al., 2005). Butovsky and colleagues have also shown that a T cell-based vaccination with glatiramer acetate resulted in decreased plaque formation and induction of neurogenesis in APP mice (Butovsky et al., 2006). The vaccination apparently exerted its effect by causing a phenotype switch of brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. These data suggest that activation of the systemic immune system is a powerful approach to treat AD and eliminate Ab from the CNS. While the phenotype switch of microglia may be contributory, the recruitment of BMDM is likely another mechanism. A better recruitment of these cells by systemic immune stimuli may therefore be envisaged as being a novel clinical tool to eliminate toxic senile plaques in the brain of AD patients. It is also possible that immunotherapy modifies resident microglia to be better phagocytes, which could be another mechanism to target the amyloid cascade (Figure 2). One can therefore be surprised by the recent clinical trial using passive immunization with humanized monoclonal anti-Ab antibody (bapineuzumab), presented by Elan/Wyeth, of an overall negative result balanced against a positive effect on a subgroup of patients who do not carry the AD risk allele ApoE4. That this phase 2 trial showed no major cognitive improvement in AD patients raises the question as to whether immunization with Ab is the direction to take. Nonetheless, it is still premature to conclude that immunization against Ab may not be effective, because this is likely to depend on the preparation, antigen target, adjuvant, and subgroup of patients. We speculate that vaccines that stimulate the hematopoietic system and microglia precursors to produce phagocytes that remove Ab will have better success to treat AD patients. In Other Brain Diseases Infiltration of bone-marrow-derived microglia has been described in other mouse models of brain diseases, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), chronic pain, prion disease, and the mouse model of MS—experimental allergic encephalomyelitis (EAE). These cells were also found in the CNS of MS and ALS patients. A marked clinical improvement has recently been reported in MS patients transplanted with autologous hematopoietic stem cells—62% of patients were disease free after 3 years (Burt et al., 2009). By contrast, unmodified hematopoietic stem cells failed to have any benefit for sporadic ALS patients (Appel et al., 2008). In mice, transplanta-

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tion of bone marrow cells from wild-type mice did not affect disease progression in either the G37R-SOD1 or G93A–SOD1 mouse model of ALS (Kang and Rivest, 2007). However, transplantation of MyD88-deficient (MyD88 pathway mediates microglial activation and infiltration) bone marrow cells dramatically changed the disease onset and progression, but only in mice that express human mutant G37R (Kang and Rivest, 2007). G37R-SOD1 mice that received MyD88-competent bonemarrow-derived microglia developed the disease later, survived longer, and had less neurodegeneration than those that were transplanted with MyD88-deficient bone marrow cells (Kang and Rivest, 2007). The results from the chimeric mice suggest that bone-marrow-derived microglia act as a natural defense mechanism against secreted mutant SOD1. Vaccination against SOD1 is also protective in mouse models of ALS (Urushitani et al., 2007). We have also found beneficial effects of MyD88-competent BMDM in mouse models of AD (K. Richard and S.R., unpublished data). Since toxic proteins are produced in many diseases, including those associated with abnormal prions, it is tempting to propose a similar beneficial role for innate immune cells in reducing neuropathology associated with secreted toxic molecules. Harnessing the Benefits of Inflammation for Repair The above discussion emphasizes the benefits of BMDM in removing toxic materials to confer protection to neurons. Other immune subsets, such as T lymphocytes, also confer neuroprotection and, in some context, repair. Through a process referred to as ‘‘protective autoimmunity,’’ autoreactive T cells protected local axons and neurons from degenerating after a traumatic injury to the spinal cord (Schwartz et al., 1999), even while other areas of the CNS were subjected to undesirable consequences of autoreactive immune cells. In normal hippocampal neurogenesis, immune activity is required since neurogenesis is impaired in T cell-deficient mice; the restoration of T cell activity improved the number of adult neurons and spatial learning (Ziv and Schwartz, 2008). Akin to the repair function of inflammation in other tissues, neuroinflammation has also been observed to confer regeneration of the nervous system. Remyelination, which is a repair process that occurs quite robustly in the mammalian CNS, is impaired in demyelinated mice that are devoid of T cells, macrophages, particular cytokines such as TNF-a and IL-1b, or leukocyte-derived proteases such as the matrix metalloproteinases (MMPs) (Yong, 2005). Axonal regeneration has also been reported to be facilitated by immune subsets, and a macrophage-derived factor that promotes axonal regeneration after optic nerve crush injury has been identified to be oncomodulin (Yin et al., 2006). The mechanisms by which immune cell subsets confer neuroprotection or recovery remain speculative, but leukocytes are known to express a range of neurotrophic factors, including the neurotrophin class of survival and regenerative factors for neural cells during development and in adulthood. It is pertinent that even in the classic inflammatory disease of the CNS, MS, where extensive and dysfunctional immune reactivity contribute to the pathology, many of the immune cells that accumulate in the CNS express neurotrophic factors. Other beneficial

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Perspective Table 1. Mechanisms of the Benefits of Inflammatory Cells in the CNS  Clearance of cellular debris as a prelude to repair  Detoxification and clearance of toxic molecules, including Ab, SOD1, and prions  Provision of a spectrum of neurotrophic factors  Removal of nonpermissive proteoglycans that hinder axonal regeneration or remyelination  Bone-marrow-derived stem cells may contribute to repopulation of neural cells

mechanisms of immune cells for the CNS (Table 1) include their clearance of toxic molecules as aforementioned and the removal of cellular debris as a prelude to repair (Figure 3). Moreover, bone marrow stem cells may differentiate to repopulate neural cells even though evidence is lacking for this phenomenon. Furthermore, leukocytes produce MMPs that can remove nonpermissive extracellular matrix proteins such as the NG2 proteoglycan (Yong, 2005) to result in a milieu that is more conducive for repair processes. Given the beneficial aspects of inflammatory cells, one is faced with the dilemma of using immunomodulators that downregulate systemic immunity even in inflammatory disorders of the CNS such as MS. We would posit that it is appropriate to use immunomodulators when the CNS is besotted by extensive numbers and activity of immune cells, since it is necessary to reduce neuroinflammation to a homeostatic level, even if one loses out on the beneficial aspects of immune cells. The challenge is when to stop the use of potent anti-inflammatory agents, since their long-term use may chronically reduce beneficial immune cells and thus compromise CNS integrity. Indeed, there are several examples in the literature of corticosteroid use that has resulted in impaired neuroprotection or remyelination in animal models. Is it possible to stimulate inflammatory processes safely for repair, particularly in inflammatory diseases such as MS? We believe that this is possible, given the improved understanding

of less proinflammatory immune cell subsets such as M2 monocytes and CD4+ T helper 2 cells that produce anti-inflammatory cytokines while producing neurotrophic factors that is a feature of all leukocyte subsets. Indeed, the MS medication glatiramer acetate generates both subsets, and we were able to demonstrate that its administration to mice with demyelination of the spinal cord resulted in increased levels of neurotrophic factors in the injured spinal cord correspondent with a greater extent of remyelination (Skihar et al., 2009). Concluding Remarks It is clear that a better understanding of the role of subpopulations of microglia/macrophages and lymphocytes in the brain is required before we can safely develop new treatments to stimulate their infiltration for preventing neuronal damage, improving repair, and eliminating toxic proteins. Moreover, we have yet to unravel the mechanisms by which these cells can be recruited in a more efficient manner without having side effects associated with their inflammatory characteristics. This remains a major challenge ahead due to possible drawbacks of immune cells and molecules on neuronal elements. It is also crucial to unravel how microglia/macrophages interact with specific Ab isoforms and other toxic proteins involved in chronic brain diseases. We will then have more specific targets to modify and ultimately prevent neuronal damages associated with accumulation of these molecules in the extracellular milieu. The field of harnessing beneficial inflammation is new, but it promises to hold great potential to confer several beneficial outcomes for the injured CNS across a variety of disorders, including those classically associated with inflammation, such as MS. One is hard-pressed to think of better strategies to protect and regenerate the CNS than to use an endogenous system that has withstood evolutionary pressures: inflammation. ACKNOWLEDGMENTS The Canadian Institutes of Health Research (CIHR), NeuroScience Canada (Brain repair program), and the MS Society of Canada support this research.

Figure 3. Beneficial Inflammation Heals CNS Injury through Several Mechanisms

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Perspective V.W.Y. and S.R. are both holders of the Canada Research Chair in Neuroimmunology.

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