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The Pathophysiological Role of Microglia in Dynamic Surveillance, Phagocytosis and Structural Remodeling of the Developing CNS

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Review

The Pathophysiological Role of Microglia in Dynamic Surveillance, Phagocytosis and Structural Remodeling of the Developing CNS

Cataldo Arcuri et al. Front Mol Neurosci.

Abstract

In vertebrates, during an early wave of hematopoiesis in the yolk sac between embryonic day E7.0 and E9.0, cells of mesodermal leaflet addressed to macrophage lineage enter in developing central nervous system (CNS) and originate the developing native microglial cells. Depending on the species, microglial cells represent 5-20% of glial cells resident in adult brain. Here, we briefly discuss some canonical functions of the microglia, i.e., cytokine secretion and functional transition from M1 to M2 phenotype. In addition, we review studies on the non-canonical functions of microglia such as regulation of phagocytosis, synaptic pruning, and sculpting postnatal neural circuits. In this latter context the contribution of microglia to some neurodevelopmental disorders is now well established. Nasu-Hakola (NHD) disease is considered a primary microgliopathy with alterations of the DNAX activation protein 12 (DAP12)-Triggering receptor expressed on myeloid cells 2 (TREM-2) signaling and removal of macromolecules and apoptotic cells followed by secondary microglia activation. In Rett syndrome Mecp2-/- microglia shows a substantial impairment of phagocytic ability, although the role of microglia is not yet clear. In a mouse model of Tourette syndrome (TS), microglia abnormalities have also been described, and deficient microglia-mediated neuroprotection is obvious. Here we review the role of microglial cells in neurodevelopmental disorders without inflammation and on the complex role of microglia in developing CNS.

Keywords: Nasu-Hakola disease; Rett syndrome; autism spectrum disorders; immunosurveillance; microglia phagocytosis; synaptic pruning.

Figures

FIGURE 1
FIGURE 1
Microglial cells. In physiological conditions and during CNS development, microglia are surveillant cells showing a ramified morphology and, according to the monocytic/macrophage lineage, express on their membrane surface β2-integrins (CD11a, CD11b), Fc receptors, and PRRs including TLRs, and P2Rs and RAGE. The surveillant state is maintained through inhibitor signals mediated by the interactions between CD200 and CD200R, CD22 and CD45, and between CX3CL1 and CX3CR1 and is characterized by the release of IGF-1, BDNF, TGF-β and NGF. Following recognition of PAMPs such as LPS, viral envelops, bacterial cell wall components, the DAMPs nuclear protein HMGB1 and S100B, NTPs or complement proteins, microglia shift to the classical activated state (known as M1 phenotype) which is characterized by the upregulation of the MHC class II and by the release of pro-inflammatory cytokines, i.e., IL-1β, IL-6, TNF-α, INF-γ and IL-15. However, in order to limit neuronal damage, the inflammation needs to be tightly regulated. Thus, after the induction of the immune response, microglial cells shift to the alternative activated state (knows as M2 phenotype) which is characterized by the induction of Arginase 1 (that promotes wound healing), heparin-binding lectin, and chitinase 3 (that prevents the degradation of extracellular matrix found in inflammatory zone and favors the deposition of extracellular matrix), and by the release of the anti-inflammatory cytokines IL-10, TGF-β and of the growth factor IGF-1.
FIGURE 2
FIGURE 2
Phagocytosis mediated by receptors. Microglial phagocytosis needs principally two type receptors: TREM2 and TLRs. TREM2 recognizes apoptotic cell debris and, through the binding to DAP12, induces F-actin reorganization and ERK phosphorylation, resulting in apoptotic neuron clearance. TLRs recognize structurally conserved molecules of microbes, DAMPs and α-synuclein. The activation of TLRs results in the induction of the MyD88-dependent pathway that, through IRAK-4 and p38 phosphorylation, induces the upregulation of scavenger receptors. TLRs also contribute to phagocytosis through a MyD88-independent actin-Cdc42/Rac pathway. However, P2Y6 receptor also contributes to UDP-evoked microglial phagocytosis through the activation of phospholipase C (PLC) that in turn triggers InsP3 synthesis-dependent Ca2+ release from InsP3-receptor-sensitive stores. In addition, P2Y6-receptor-dependent signaling promotes actin cytoskeleton polarization facilitating the engulfment of cell debris.
FIGURE 3
FIGURE 3
Phagocytosis mediated by the exposure of “eat-me” and “don’t-eat-me” signals. In addition to receptor activation, microglial phagocytosis is also triggered by the exposure of “eat-me” and “don’t-eat-me” signals. Among “eat-me” signals there is the exposure of PS on neurons following oxidative stress, increase in Ca2+ levels or ATP depletion; PS binds VNRs through the interaction with MFG-E8. PS also binds MERTK through the interaction with both GAS6 and Protein S. Calreticulin is another neuronal “eat-me” signal that binds LRPs on microglial cells. Also the complement components C1q and Cb3 induce phagocytosis; C1q binds de-sialylated neuronal glicoproteins and is recognized by LRPs in association with calreticulin, whereas C3b binds C3R. Microglial phagocytosis is inhibited by inhibitory signals referred to as “don’t-eat-me” signals mediated by the interaction between CD47 and SIRPα and between polysialylated proteins and SIGLECs.
FIGURE 4
FIGURE 4
Contribution of microglial cells in physiologic and pathologic conditions. (A) During CNS development, microglial cells are responsible for the immune surveillance and are involved in the regulation of the development of other CNS cell types, neural stem cell proliferation, neuronal programmed cell death, embryonic brain wiring and synaptic pruning. (B) Microglial cells play a central role in many neurodevelopmental diseases. Some of these disturbances, such as Nasu-Hakola disease, Rett syndrome, Fragile X syndrome and Phelan-Mc Dermic syndrome are characterized each by one well known genetic alteration while others such as Autistic Spectrum Disorders originate from the interactions between genetic alteration arbored by microglial cells and epigenetic factors; however, both conditions are characterized by a sustained production of pro-inflammatory cytokines, alterations in phagocytosis mechanisms and defective synaptic pruning. (C) Microglial cells are also involved in some CNS diseases typical of the adult such as Alzheimer’s disease, characterized by inappropriate pro-inflammatory immune response.
FIGURE 5
FIGURE 5
Schematic representation of the contribution of microglial cells to Rett syndrome, Tourette syndrome and Nasu-Hakola disease. (A) Impaired phagocytosis due to alteration or loss of Mecp2 expression and the consequent accumulation of neuronal debris contribute to the development of Rett syndrome without the induction of a pro-inflammatory response. Moreover, the high levels of glutamate produced and released by microglial cells may cause the adverse effects on neuronal function observed in Rett syndrome. (B) The behavioral and neurochemical abnormalities observed in Tourette syndrome might be associated with a reduction of microglial cells expressing IGF-1 that results in an impaired neurotrophic protection of neurons. (C) Aberrant expression of TREM2 and DAP12 in microglial cells is considered tightly related to the inhibition of apoptotic neuron clearance observed in Nasu-Hakola disease. Impaired phagocytosis could be responsible for the excessive pro-inflammatory activation of microglial cells resulting in neurodegeneration with amyloid plaque deposition and early FTD.

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References

    1. Abbott N. J., Patabendige A. A., Dolman D. E., Yusof S. R., Begley D. J. (2010). Structure and function of the blood-brain barrier. Neurobiol. Dis. 37 13–25. 10.1016/j.nbd.2009.07.030 - DOI - PubMed
    1. Aderem A., Underhill D. M. (1999). Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17 593–623. 10.1146/annurev.immunol.17.1.593 - DOI - PubMed
    1. Ajami B., Bennett J. L., Krieger C., Tetzlaff W., Rossi F. M. (2007). Local self- renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10 1538–1543. 10.1038/nn2014 - DOI - PubMed
    1. Alliot F., Godin I., Pessac B. (1999). Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117 145–152. 10.1016/S0165-3806(99)00113-3 - DOI - PubMed
    1. Alliot F., Lecain E., Grima B., Pessac B. (1991). Microglial progenitors with a high proliferative potential in the embryonic and adult mouse brain. Proc. Natl. Acad. Sci. U.S.A. 88 1541–1545. 10.1073/pnas.88.4.1541 - DOI - PMC - PubMed

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