Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis
TL;DR: The cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotroph lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.
Abstract: Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25+/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.
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TL;DR: It is argued that therapeutic approaches targeting cerebral inflammation should shift from broad suppression of microglia and macrophages towards subtle adjustment of the balance between their phenotypes, and breakthroughs in the identification of regulatory molecules that control these phenotypic shifts could ultimately accelerate research towards curing brain disorders.
Abstract: The traditional view of the adult brain as a static organ has changed in the past three decades, with the emergence of evidence that it remains plastic and has some regenerative capacity after injury. In the injured brain, microglia and macrophages clear cellular debris and orchestrate neuronal restorative processes. However, activation of these cells can also hinder CNS repair and expand tissue damage. Polarization of macrophage populations toward different phenotypes at different stages of injury might account for this dual role. This Perspectives article highlights the specific roles of polarized microglial and macrophage populations in CNS repair after acute injury, and argues that therapeutic approaches targeting cerebral inflammation should shift from broad suppression of microglia and macrophages towards subtle adjustment of the balance between their phenotypes. Breakthroughs in the identification of regulatory molecules that control these phenotypic shifts could ultimately accelerate research towards curing brain disorders.
977 citations
TL;DR: New findings in ALS research are summarized, what they have taught us about this disease are discussed and issues that are still outstanding are examined.
Abstract: Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.
884 citations
TL;DR: The roles of inflammatory response in neurodegenerative diseases are discussed, focusing on the contributions of microglia and astrocytes and their relationship, and biomarkers to measure neuro inflammation and studies on therapeutic drugs that can modulate neuroinflammation are discussed.
Abstract: Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.
616 citations
TL;DR: It is indicated that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.
Abstract: Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1G93A mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1G93A mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.
561 citations
Cites background from "Endogenous regulatory T lymphocytes..."
...transiently enhanced at the presymptomatic phase of ALS, whereas M1 microglia markers are gradually increased during the disease progression.(13) However, the mechanisms reg-...
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TL;DR: It is found that SOD1(G93A) microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer's disease genes, are concurrently upregulated.
526 citations
Cites background from "Endogenous regulatory T lymphocytes..."
...During disease progression in SOD1G93A mice, microglia have been reported to adopt an M2 protective phenotype that transitions to an M1 neurotoxic phenotype over time (Beers et al., 2011; Vaknin et al., 2011)....
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...Despite ontological differences between microglia and peripheral macrophages, microglia have also been categorized as M1- or M2-like (Appel et al., 2011; Beers et al., 2011)....
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...Nonetheless, microglia have often been designated as M1 or M2 macrophage-like (Beers et al., 2008, 2011; Hickman et al., 2008; Ransohoff and Perry, 2009)....
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...During disease progression in SOD1 mice, microglia have been reported to adopt an M2 protective phenotype that transitions to an M1 neurotoxic phenotype over time (Beers et al., 2011; Vaknin et al., 2011)....
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...Although microglia are ontologically distinct from peripheral macrophages, they have nevertheless been classified as M1or M2-like in ALS and Alzheimer’s disease (AD) (Beers et al., 2011; Hickman et al., 2008; Michelucci et al., 2009)....
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References
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TL;DR: It is shown that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β, and the data demonstrate a dichotomy in thegeneration of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T Cells that inhibit autoimmune tissue injury.
Abstract: On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.
6,643 citations
"Endogenous regulatory T lymphocytes..." refers background in this paper
...FoxP3 fluorescent intensity, an assess- ment of the level of FoxP3 expression in lymphocytes, was increased in blood CD25 +FoxP3+ Tregs at 11, 14 and 16 weeks, but was at wild-type levels at 18 weeks and thereafter (Fig....
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...CD4 +CD25 + and CD25 + FoxP3+ Tregs were increased in the blood of mSOD1 mice at every time point analysed, peaking at 16 weeks (Fig....
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...The transformation from protection to toxicity may coincide with the expression of IL-6; IL-6 completely inhibits the generation of FoxP3 Tregs (Bettelli et al., 2006)....
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...The transformation from protection to toxicity may coincide with the expression of IL-6; IL-6 completely inhibits the generation of FoxP3+ Tregs (Bettelli et al., 2006)....
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...In lymph nodes, CD4 +CD25 + and CD25 + FoxP3+ Tregs were increased between 16 and 20 weeks; CD25 + FoxP3+ Tregs were only increased in the spleens of mSOD1 mice at end stage disease (Fig....
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TL;DR: The cellular and molecular basis of Treg development and function is revealed and dysregulation of T Regs in immunological disease is implicates.
4,427 citations
"Endogenous regulatory T lymphocytes..." refers background in this paper
...Since Tregs are known to produce IL-10, we next asked whether IL-10 released by Tregs plays a role in suppressing micro- glial toxic functions (Sakaguchi et al., 2008)....
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...The suppressive effects of CD4 +CD25 + FoxP3+ regulatory T lymphocytes (Tregs) on the adaptive and innate immune systems have been documented (Sakaguchi et al., 2005, 2008; Tiemessen et al., 2007)....
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TL;DR: In this article, the authors found that mutations of human Cu,Zn superoxide dismutase (SOD) contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS).
Abstract: Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral sclerosis (ALS). Expression of high levels of human SOD containing a substitution of glycine to alanine at position 93--a change that has little effect on enzyme activity--caused motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. The results show that dominant, gain-of-function mutations in SOD contribute to the pathogenesis of familial ALS.
3,958 citations
TL;DR: In this paper, the authors assess recent research in this field, argue for a restricted definition, and explore pathways by which the T helper 2 (Th2) cell cytokines interleukin-4 (IL-4) and IL-13 mediate their effects on macrophage cell biology, their biosynthesis, and responses to a normal and pathological microenvironment.
3,450 citations
Additional excerpts
...CD206, also known as the mannose receptor, c type 1 or MRC1, was assayed as another marker for M2 microglia (Colton et al., 2006; Tiemessen et al., 2007; Gordon and Martinez, 2010)....
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TL;DR: Naturally arising CD25+CD4+ regulatory T cells actively maintain immunological self-tolerance, and are a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.
Abstract: Naturally arising CD25+CD4+ regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance. They are therefore a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.
2,683 citations