P2Y12R-Dependent Translocation Mechanisms Gate the Changing Microglial Landscape

Eyo, Ukpong B.; Mo, Mingshu; Yi, Min; Murugan, Madhuvika; Liu, Junting; Yarlagadda, Rohan; Margolis, David J.; Xu, Pingyi; Wu, Long Jun

doi:10.1016/j.celrep.2018.04.001

Cited by 107 publications

(111 citation statements)

References 35 publications

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“…Seizure‐induced activation of microglia was, expectedly, characterized by time‐dependent changes in the morphological state including increase in microglial cell number, increased soma size and reduction in number of processes/process length (Avignone et al, ; Eyo et al, ). However, we found that infiltrated monocytes after status epilepticus lacked cellular processes and were highly motile cells when compared to the relatively stationary microglial (Eyo et al, ). Interestingly, microglia and monocytes showed distinct electrophysiological properties as well.…”

Section: Discussionmentioning

confidence: 99%

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

Feng

Murugan

Bosco

et al. 2019

Glia

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Microglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1GFP/+ CCR2RFP/+ genetic mouse model, in which CX3CR1+ resident microglia and CCR2+ monocytes are labeled with GFP and RFP, respectively. Using a combination of time‐lapse two‐photon imaging and whole‐cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid‐induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony‐stimulating factor 1 receptor (CSF‐1R) pathway. Pharmacological inhibition of CSF‐1R reduced seizure‐induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF‐1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy.

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Section: Discussionmentioning

confidence: 99%

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

Feng

Murugan

Bosco

et al. 2019

Glia

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“…This implies that microglia could proliferate multiple times during the first 3 d. Alternatively, it is also possible that microgliosis could be due to migration of SDH microglia from neighboring spinal segments (e.g., rostral L3 and caudal L5 segments) because microglia show chemotaxis. 31,32) However, infiltration of circulating monocytes in the SDH, 12) which is reported to express Iba1, does not contribute to the PNI-induced SDH microgliosis, since recent studies using bone marrow chimeric mice subjected to mild irradiation, parabiosis mice and doubletransgenic mice (enable distinct visualization of resident microglia and circulating monocytes) demonstrated no evidence for the involvement of circulating monocytes. 4,10,11) Numerous microglia induced by PNI gradually returned to pre-PNI levels, the time-course of which is similar to a recovery of PNI-induced pain hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Kohno

Kitano

Kohro

et al. 2018

Biological & Pharmaceutical Bulletin

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Neuropathic pain, a highly debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. Previous studies have implicated activated microglia in the spinal dorsal horn (SDH) as key cellular intermediaries in neuropathic pain. Microgliosis is among the dramatic cellular alterations that occur in the SDH in models of neuropathic pain established by peripheral nerve injury (PNI), but detailed characterization of SDH microgliosis has yet to be realized. In the present study, we performed a short-pulse labeling of proliferating cells with ethynyldeoxyuridine (EdU), a marker of the cell cycle S-phase, and found that EdU microglia in the SDH were rarely observed 32 h after PNI, but rapidly increased to the peak level at 40 h post-PNI. Numerous EdU microglia persisted for the next 20 h (60 h post-PNI) and decreased to the baseline on day 7. These results demonstrate a narrow time window for rapidly inducing a proliferation burst of SDH microglia after PNI, and these temporally restricted kinetics of microglial proliferation may help identify the molecule that causes microglial activation in the SDH, which is crucial for understanding and managing neuropathic pain.Key words proliferation; microgliosis; spinal dorsal horn; neuropathic pain; peripheral nerve injury Neuropathic pain is a debilitating chronic pain state caused by damage to the nervous system incited by cancer, diabetes, chemotherapy and trauma. One of the hallmark symptoms is mechanical allodynia (non-nociceptive mechanical stimuli elicit pain), and neuropathic pain is often resistant to currently available therapies. 1) Injury to peripheral nerves of rodents, which are frequently used as models of neuropathic pain, produces mechanical pain hypersensitivity and alterations at molecular and cellular levels that result in multiple forms of neuronal plasticity and structural reorganization, not only in the affected sensory ganglion cell body, but also in the spinal dorsal horn (SDH). 2,3) The peripheral nerve injury (PNI)-induced alterations in the SDH are observed not only in neurons, but also in glial cells, especially microglia, which are known as resident immune cells in the central nervous system (CNS). Following PNI, SDH microglia become activated through a progressive series of changes in their morphology, expression of a variety of genes and cell number. 4) One of the most prominent features of microglial activation is an increase in the number of microglia (called microgliosis). Since PNI-induced microgliosis in the SDH was recorded in 1970s 5) and the rodent models of neuropathic pain were established in 1990s, 6-9) studies have investigated the mechanism for microgliosis in the SDH after PNI. Two possible mechanisms (proliferation of resident microglia 10,11) and infiltration of bone marrow-derived monocytes 12) ) have been considered, but it is now thought that local expansion of resident microglia by proliferation is the primary cellular basis for SDH microgliosis after PNI...

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“…A gradient or threshold of these factors may start intracellular cascades in microglia that trigger division and migration, such as NF-KB signaling which has been shown to be important for microglia to repopulate fully . In addition, we show that the P2Y12 receptor is not critical to doublet formation, repopulation, or the acquisition of microglial territories (as reflected by changes in nearest neighbor quantification) in the visual cortex (Figure 2 and 3), which is surprising given that P2Y12 modulates microglial translocation in baseline conditions (Eyo et al, 2018). The progressive distribution of microglia to achieve tiling during repopulation is most likely maintained by lateral inhibition mechanisms and homeostatic microglia-specific genes such as Sal1 and Mafb-which both maintain microglia in a ramified nonclustered state (Buttgereit et al, 2016; Matcovitch-Natan et al, 2016).…”

Section: Intrinsic and Extrinsic Mechanisms Of Microglia Repopulationmentioning

confidence: 77%

“…In both the rodent and human brain, microglial numbers are maintained throughout adult life (Fuger et al, 2017;Hashimoto et al, 2013;Reu et al, 2017), with no further contribution of peripheral cells to the microglial population in the absence of pathological changes (Ajami et al, 2007;Askew et al, 2017;Bruttger et al, 2015;Elmore et al, 2015;Mildner et al, 2007). Microglia are uniformly distributed in a distinct cellular grid throughout the brain parenchyma (Eyo et al, 2018;Hefendehl et al, 2014;Nimmerjahn et al, 2005) and maintain their territories with slow translocation on a timescale of days (Eyo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

In vivoimaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

Mendes

Atlas

Ladrón-de-Guevara

et al. 2020

Preprint

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Microglia are the resident immune cells in the brain with the capacity to autonomously self-renew. Under basal conditions, microglial self-renewal appears to be slow and stochastic, although microglia have the ability to proliferate very rapidly following depletion or in response to injury. Because microglial self-renewal has largely been studied using static tools, the mechanisms and kinetics by which microglia renew and acquire mature characteristics in the adult brain are not well understood. Using chronic in vivo two-photon imaging in awake mice and PLX5622 (Colony stimulating factor 1 receptor (CSF1R) inhibitor) to deplete microglia, we set out to understand the dynamic self-organization and maturation of microglia following depletion in the visual cortex. We confirm that under basal conditions, cortical microglia show limited turnover and migration. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of the remaining microglia in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly-born microglia resemble mature microglia, in terms of their morphology, dynamics and ability to respond to injury, within days of repopulation. Our work suggests that microglia rapidly self-renew locally, without the involvement of a special progenitor cell, and that newly born microglia do not recapitulate a slow developmental maturation but instead quickly take on mature roles in the nervous system.

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P2Y12R-Dependent Translocation Mechanisms Gate the Changing Microglial Landscape

Cited by 107 publications

References 35 publications

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

In vivoimaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

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