Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice

Graduate Program in Neuroscience, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 03/2011; 25(3):379-85. DOI: 10.1016/j.bbi.2010.11.009
Source: PubMed


It was recently shown that adaptive immunity plays a key role in cognitive function. T cells appear to be major players in learning and memory; thus, mice devoid of functional T cells are impaired in performance of cognitive tasks such as Morris water maze (MWM), Barnes maze and others. This is a reversible phenomenon; injection of immune deficient mice with T cells from wild type counterparts improves their cognitive function. Recently we described a critical role for T cell-derived IL-4 as having beneficial effects on learning and memory through regulation of meningeal myeloid cell phenotype. In the absence of IL-4, meningeal myeloid cells acquire a pro-inflammatory skew. Thus, the presence of IL-4 in the meningeal spaces maintains a delicate balance of pro- and anti-inflammatory myeloid cell phenotype. Here we show that macrophages alternatively activated in vitro (M2 cells) can circumvent the need for 'pro-cognitive' T cells when injected intravenously into immune deficient mice. These results show for the first time that M2 myeloid cells are new and unexpected players in cognitive function, conferring beneficial effects on learning and memory without adaptive immune influence. These results might lead to development of new therapeutic approaches for cognitive pathologies associated with malfunction of adaptive immunity, such as chemo-brain, age-related dementia, HIV-dementia, and others.

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Available from: Noel Derecki, Dec 03, 2014
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    • "Mice that lack IL-4 demonstrated cognitive impairment in spatial learning tasks; after transplantation with IL-4 competent bone marrow, this impairment was reversed [34]. A proposed mechanism by which IL-4 promotes cognition is that it exerts its effect through an anti-inflammatory M2-skew of meningeal macrophages, which has been shown to be both beneficial after CNS injury [35] and required for learning [36]. These findings support the concept that a pro-inflammatory state can be detrimental to the developing brain and suggest a potential role for IL-4 in tissue repair and neuroprotection. "
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    ABSTRACT: An estimated one-third of children younger than 5 in low- and middle-income countries fail to meet their full developmental potential. The first year of life is a period of critical brain development and is also when most of the morbidity from infection is suffered. We aimed to determine if clinical and biological markers of inflammation in the first year of life predict cognitive, language, and motor outcomes in children living in an urban slum in Bangladesh. Children living in Dhaka, Bangladesh were observed from birth until 24 months of age. Febrile illness was used as a clinical marker of inflammation and elevated concentrations of inflammation-related cytokines (IL-1beta, IL-6, TNF-alpha, IL-4, IL-10) in sera collected from a subset of the cohort (N = 127) at 6 months of age were used as biomarkers of inflammation. Psychologists assessed cognitive, language, and motor development using a culturally adapted version of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 12 (N = 398) and 24 months of age (N = 210). We tested for the ability of febrile illness and elevated cytokine levels to predict developmental outcomes, independent of known predictors of stunting, family income, and maternal education. Every additional 10 days of fever was associated with a 1.9 decrease in language composite score and a 2.1 decrease in motor composite score (p = 0.005 and 0.0002, respectively). Elevated levels of the pro-inflammatory cytokines IL-1beta (> 7.06 pg/mL) and IL-6 (> 10.52 pg/mL) were significantly associated with a 4.9 and 4.3 decrease in motor score, respectively. Conversely, an elevated level of the Th-2 cytokine IL-4 (> 0.70 pg/mL) was associated with a 3.6 increase in cognitive score (all p < 0.05). Clinical and biological markers of inflammation in the first year of life were significantly associated with poor neurodevelopmental outcomes. Conversely, a Th2-like response was associated with a better outcome. These findings suggest that markers of inflammation could serve as prognostic indicators and potentially lead to immune-based therapies to prevent developmental delays in at-risk children.
    BMC Pediatrics 02/2014; 14(1):50. DOI:10.1186/1471-2431-14-50 · 1.93 Impact Factor
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    • "The authors were the first to describe a critical role for T cell derived IL-4 as key cytokine involved in learning and memory through regulation of myeloid cells present in the meningeal space (32, 57). This intriguing new concept has been recently confirmed by showing improved learning and memory in T cell deficient SCID mice adoptively transferred with M2 macrophages (58). Considering the well-known crosstalk between cognition and emotion regulation (31), it would be interesting to explore the possible changes in myeloid cell phenotype during the early stages of the EAE. "
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    ABSTRACT: Autoimmune diseases like multiple sclerosis (MS) are known to be associated with debilitating emotional disorders that manifest long before the flaring of motor dysfunctions. Given the emerging role of T cells in controlling both emotions and autoimmunity, in this study we explored possible correlation between T cell activation and changes in emotional behavior in a mouse model of MS. Our results showed a significant increase in blood circulating T cells as soon as at day 4 post immunization. This lymphocytosis remained stable with time and preceded the infiltration of T cell in the CNS. The kinetic of T cell entry in the blood matched the kinetic of changes in behavior measured using the open field test. Treatment with glatiramer acetate, a well-known immunomodulatory drug for MS, suppressed behavioral changes while retaining the T cells in the draining lymph nodes. Together these results provide evidence of a positive correlation between the emigration of T cells in circulation and changes in emotions during chronic inflammatory diseases. The validation of these findings in the clinic might help to better understand the cause of the emotional and psychological burden of patients suffering MS or other autoimmune diseases. Most importantly our study suggests novel therapeutic venues for the treatment of the emotional changes associated with autoimmunity.
    Frontiers in Immunology 11/2013; 4:400. DOI:10.3389/fimmu.2013.00400
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    • "These neurobiological functions are thought to contribute to blood-derived macrophages support of learning and memory (as determined via the Morris Water Maze and Barnes Maze; Derecki et al., 2010, 2011). Importantly, intravenous injection of M2 cells into immune-deficient mice can circumvent the need for CNS-specific autoreactive CD4+ T cells (Derecki et al., 2011). For a review of the role of blood-derived macrophages see recent papers (Derecki et al., 2010; Martino et al., 2011; Yirmiya and Goshen, 2011). "
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    ABSTRACT: The increasing burden of major depressive disorder makes the search for an extended understanding of etiology, and for the development of additional treatments highly significant. Biological factors may be useful biomarkers for treatment with physical activity (PA), and neurobiological effects of PA may herald new therapeutic development in the future. This paper provides a thorough and up-to-date review of studies examining the neuroimmunomodulatory effects of PA on the brain in depression and depression-like behaviors. From a neuroimmune perspective, evidence suggests PA does enhance the beneficial and reduce the detrimental effects of the neuroimmune system. PA appears to increase the following factors: interleukin (IL)-10, IL-6 (acutely), macrophage migration inhibitory factor, central nervous system-specific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and insulin-like growth factor-1. On the other hand, PA appears to reduce detrimental neuroimmune factors such as: Th1/Th2 balance, pro-inflammatory cytokines, C-reactive protein, M1 microglia, and reactive astrocytes. The effect of other mechanisms is unknown, such as: CD4+CD25+ T regulatory cells (T regs), CD200, chemokines, miRNA, M2-type blood-derived macrophages, and tumor necrosis factor (TNF)-α [via receptor 2 (R2)]. The beneficial effects of PA are likely to occur centrally and peripherally (e.g., in visceral fat reduction). The investigation of the neuroimmune effects of PA on depression and depression-like behavior is a rapidly developing and important field.
    Frontiers in Psychiatry 02/2013; 4:3. DOI:10.3389/fpsyt.2013.00003
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