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

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

Noel C Derecki et al. Brain Behav Immun. 2011 Mar.

Abstract

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.

Copyright © 2010 Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1. Generation, characterization and intracerebroventricular injection of alternatively activated macrophages

(a) Representative image of alternatively activated bone marrow-derived macrophages after nine days in culture. (b) FACS analysis of M1 and M2 skewed macrophages labeled for TNFα and CD206 expression. (c) Representative images of CFSE-labeled macrophages in ventricles 3d after i.c.v. injection are shown.

Figure 2
Figure 2. I.c.v. injection of M2 cells into SCID mice marginally benefits MWM performance

SCID mice (C57BL/6J) were injected i.c.v. with either M2-skewed macrophages (N=8) or ACSV vehicle (N=8) and monitored during MWM task performance. (a) During the acquisition and (b) the probe trial phases, no significant difference between the two groups was obtained. (c) During the reverse phase, M2-injected mice took significantly less time to locate the hidden platform as compared to their controls. Two-way repeated measures ANOVA with post hoc Bonferroni test was used for statistical analysis (**, p < 0.01). All behavior experiments were recorded with the EthoVision video tracking system and performed by an experimenter blinded to the identity of experimental groups. Representative experiments are shown out of two independently performed.

Figure 3
Figure 3. I.c.v. injection of M2 cells into SCID mice results in an anti-inflammatory skew of endogenous meningeal myeloid cells

FACS analyses were performed on viable, CD45+/CD11b+ cells isolated from (a, c) meninges and (b) spleen of MWM-trained mice. Numbers on histograms indicate percentages. CD11b+ cells from both spleens and meninges of M2-injected animals showed up-regulation of CD206 as compared to vehicle-injected control. (c) Endogenous meningeal myeloid cells of M2-injected animals also displayed decreased production of the pro-inflammatory cytokine TNFα and increased production of anti-inflammatory IL-10. Representative experiment out of two independently performed is presented (n = 8 mice in each group).

Figure 4
Figure 4. Intravenous injection of M2 improves cognitive performance of SCID mice on MWM task

SCID mice (C57BL/6J) were injected i.v. with either M1-skewed macrophages, M2-skewed macrophages or PBS vehicle (N=8 in each group) and monitored during MWM task performance. During (a) the acquisition and (c) the reversal phases of the task, M2-injected mice took significantly less time than M1- or vehicle-injected controls to locate the hidden platform. Two-way repeated measures ANOVA with post hoc Bonferroni test was used for statistical analysis (**, p < 0.01). (b) During the probe trial, M2-injected mice spent significantly more time in the training quadrant than M1- or vehicle-injected controls. Student's t-test; (*, p < 0.05). Representative experiments are shown out of two independently performed.

Figure 5
Figure 5. I.v. injection of M2 cells into SCID mice results in an anti-inflammatory skew of endogenous meningeal myeloid cells

FACS analyses were performed on viable, CD45+/CD11b+ cells isolated from (a-c) meninges and (d-f) spleen of MWM-trained mice. Numbers on histograms indicate percentages. CD11b+ cells from both spleens and meninges of M1- or M2- injected animals and their vehicle-injected controls were examined for (a, d) Ly6C, (b, e) TNFα, and (c, f) IL-10 expression. Representative experiment out of two independently performed is presented (n = 8 mice in each group).

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