Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice

Program in Cellular and Molecular Biology, University of Wisconsin, Madison, Wisconsin
Journal of Neuroscience Research (Impact Factor: 2.59). 09/2013; 91(9). DOI: 10.1002/jnr.23242
Source: PubMed

ABSTRACT Although microglial activation is associated with all CNS disorders, many of which are sexually dimorphic or age-dependent, little is known about whether microglial basal gene expression is altered with age in the healthy CNS or whether it is sex dependent. Analysis of microglia from the brains of 3-day (P3)- to 12-month-old male and female C57Bl/6 mice revealed distinct gene expression profiles during postnatal development that differ significantly from those in adulthood. Microglia at P3 are characterized by relatively high iNOS, TNFα and arginase-I mRNA levels, whereas P21 microglia have increased expression of CD11b, TLR4, and FcRγI. Adult microglia (2-4 months) are characterized by low proinflammatory cytokine expression, which increases by 12 months of age. Age-dependent differences in gene expression suggest that microglia likely undergo phenotypic changes during ontogenesis, although in the healthy brain they did not express exclusively either M1 or M2 phenotypic markers at any time. Interestingly, microglia were sexually dimorphic only at P3, when females had higher expression of inflammatory cytokines than males, although there were no sex differences in estrogen receptor expression at this or any other time evaluated here. Compared with microglia in vivo, primary microglia prepared from P3 mice had considerably altered gene expression, with higher levels of TNFα, CD11b, arginase-I, and VEGF, suggesting that culturing may significantly alter microglial properties. In conclusion, age- and sex-specific variances in basal gene expression may allow differential microglial responses to the same stimulus at different ages, perhaps contributing to altered CNS vulnerabilities and/or disease courses. © 2013 Wiley Periodicals, Inc.

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    • "Recent studies have shown that activated microglia can be divided into two phenotypic profiles. The classical M1 state, characterized by proinflammatory factors for example, interleukins (IL-1Β, IL-18, and IL-6) and inducible nitric oxide synthase (NOS2) [11] [12] [13] [14], is neurotoxic and therefore contributes to secondary neuronal damage, cell death, and demyelination, which lead to neurodegeneration [15] [16]. The neuroprotective M2 state, known as " alternative activation, " is associated with the release of anti-inflammatory factors, such as IL-10, IL-4, and NGF [13] [17] [18]. "
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    ABSTRACT: Microglial activation is a polarized process divided into potentially neuroprotective phenotype M2 and neurotoxic phenotype M1, predominant during chronic neuroinflammation. Endocannabinoid system provides an attractive target to control the balance between microglial phenotypes. Anandamide as an immune modulator in the central nervous system acts via not only cannabinoid receptors (CB1 and CB2) but also other targets (e.g., GPR18/GPR55). We studied the effect of anandamide on lipopolysaccharide-induced changes in rat primary microglial cultures. Microglial activation was assessed based on nitric oxide (NO) production. Analysis of mRNA was conducted for M1 and M2 phenotype markers possibly affected by the treatment. Our results showed that lipopolysaccharide-induced NO release in microglia was significantly attenuated, with concomitant downregulation of M1 phenotypic markers, after pretreatment with anandamide. This effect was not sensitive to CB1 or GPR18/GPR55 antagonism. Administration of CB2 antagonist partially abolished the effects of anandamide on microglia. Interestingly, administration of a GPR18/GPR55 antagonist by itself suppressed NO release. In summary, we showed that the endocannabinoid system plays a crucial role in the management of neuroinflammation by dampening the activation of an M1 phenotype. This effect was primarily controlled by the CB2 receptor, although functional cross talk with GPR18/GPR55 may occur.
    06/2015; 2015:1-10. DOI:10.1155/2015/130639
    • "In recent years several studies also focused on sex dimorphisms in microglia in health and disease. The differences in number, morphology and molecular phenotype of microglia cells between the sexes evolve along the development; and could explain the differential vulnerability that females and males show for certain brain pathologies in each developmental stage (Crain et al., 2013; Lenz and McCarthy, 2014; Loram et al., 2012; Schwarz and Bilbo, 2012; Schwarz et al., 2012; Sierra et al., 2007). It is not clear whether these sex differences are due to genetic or hormonal causes; but sex hormones, estradiol, progesterone, and testosterone, are known to reduce inflammation in the nervous system by multiple and complex mechanisms that, at least in part, involve the modulation of the response of glial cells to injury (Acaz- Fonseca et al., 2014; Arevalo et al., 2010; Cerciat et al., 2010; Garcia-Segura and Melcangi, 2006; Habib and Beyer, 2014; Habib et al., 2014; Johann and Beyer, 2013; Loram et al., 2012). "
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    ABSTRACT: Several brain disorders associated with neuroinflammation show sex differences in their incidence, onset, progression and/or outcome. The different regulation of the neuroinflammatory response in males and females could underlie these sex differences. In this study, we have explored whether reactive gliosis after a penetrating cortical injury exhibits sex differences. Males presented a higher density of Iba1 immunoreactive cells in the proximity of the wound (0-220 μm) than females. This sex difference was due to a higher number of Iba1 immunoreactive cells with nonreactive morphology. In addition microglia/macrophages in that region expressed arginase-1, marker of alternatively activated microglia, and the neuroprotective protein Neuroglobin, in a greater proportion in males than in females. No sex differences were found in the number of astrocytes around the lesion. However, the percentage of astrocytes expressing chemokine (C-C motif) ligand 2 (CCL2), involved in recruitment of immune cells and gliosis regulation, was higher in males. Males also presented a significantly higher density of neurons in the lesion edge than females. These findings indicate that male and female mice have different neuroinflammatory responses after a cortical stab wound injury and suggest that sex differences in reactive gliosis may contribute to sex differences in neuroinflammatory diseases. GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Glia 06/2015; 63(11). DOI:10.1002/glia.22867 · 6.03 Impact Factor
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    • "feration ( Kotecha and Schlichter , 1999 ) , migration ( Rappert et al . , 2002 ; Schilling et al . , 2004 ) and cell process extension and retraction ( Eder et al . , 1998 ) . However , microglia activation is no longer considered an all or none event , but rather a sequence of progressive stages ( Ponomarev et al . , 2007 ; Olah et al . , 2012 ; Crain et al . , 2013 ) depending on the bal - ance between pro - inflammatory and anti - inflammatory signals in the surrounding environment ( Biber et al . , 2007 ; Lively and Schlichter , 2013 ) ."
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    ABSTRACT: Microglial cells participate in brain development and influence neuronal loss and synaptic maturation. Fractalkine is an important neuronal chemokine whose expression increases during development and that can influence microglia function via the fractalkine receptor, CX3CR1. Mice lacking Cx3cr1 show a variety of neuronal defects thought to be the result of deficient microglia function. Activation of CX3CR1 is important for the proper migration of microglia to sites of injury and into the neuropil during development. However, little is known about how fractalkine modulates microglial properties during development. Here we examined microglial morphology, response to ATP, and K+ current properties in acute brain slices from Cx3cr1 knockout mice across postnatal hippocampal development. We found that fractalkine signaling is necessary for the development of several morphological and physiological features of microglia. Specifically, we found that the occurrence of an outward rectifying K+ current, typical of activated microglia, that peaked during the second and third postnatal week, was reduced in Cx3cr1 knockout mice. Fractalkine signaling also influenced microglial morphology and ability to extend processes in response to ATP following its focal application to the slice. Our results reveal the developmental profile of several morphological and physiological properties of microglia and demonstrate that these processes are modulated by fractalkine signaling.
    Frontiers in Cellular Neuroscience 03/2015; 9. DOI:10.3389/fncel.2015.00111 · 4.29 Impact Factor
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