Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1

Madry, Christian; Kyrargyri, Vasiliki; Arancibia-Cárcamo, I. Lorena; Jolivet, Renaud; Kohsaka, Shinichi; Bryan, Robert M.; Attwell, David

doi:10.1016/j.neuron.2017.12.002

Cited by 336 publications

(467 citation statements)

References 65 publications

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“…However, SDH microglia seemed to have already responded, because morphology of microglia changed during the first 24 h: the processes of SDH microglia were retracted, and their complexity became simplified. A recent study has reported that long-term exposure (1 h) of rats to the volatile anesthetic isoflurane shortens microglial processes, 28) but under our experimental condition in which mice were anesthetized by isoflurane for a short period (approximately 15 min), the process morphology of SDH microglia was indistinguishable between sham-operated mice and naïve mice with or without anesthesia, respectively. Thus, it seems that microglia could receive a signal(s) presumably from DRG neurons at least 12 h after PNI and change their phenotype from normal surveillance to reactive.…”

Section: Discussionmentioning

confidence: 60%

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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Section: Discussionmentioning

confidence: 60%

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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“…In the healthy brain microglia efficiently monitor CNS homeostasis and have a marked impact on neural development. In order to actively survey the CNS they have recently been demonstrated to require the proper activity of tandem‐pore domain halothane‐inhibited K + channel 1, which is the main K + channel expressed in microglial cells (Madry et al, ). In several pathological conditions such as epilepsy, single‐cell RNA sequencing of hippocampal microglia indicated that microglia undergo dramatically transcriptomic alterations (more than 2,000 differentially expressed genes) and immunological activation during early time points, particularly regarding mitochondrial activity and metabolic pathways (Bosco et al, ).…”

Section: Introductionmentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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“…As previously described (Charolidi, Schilling, & Eder, ; Madry, Kyrargyri, et al, ), hippocampal slices (300 μm thick) were prepared in ice‐cold HEPES‐buffered medium (MEM bubbled with O 2 , pH 7.4, 42360‐032, Gibco) under sterile conditions. To induce inflammasome activation and IL‐1β release, slices were exposed to inflammatory‐like stimuli (Bernardino et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…It also increases the P2Y 12 ‐mediated THIK‐1 current, although the directed motility (but not the speed of individual process movements) towards an ADP source or brain injury is slower in the P2Y 13 KO mice, as the shorter processes need to grow further and thus take a longer time to reach their target. The membrane potential of P2Y 13 KO microglia is similar to that of WT microglia, indicating that the deramified morphology is not due to voltage changes (Madry, Kyrargyri, et al, ), but has some aspects of a “primed‐like” microglial phenotype. This is further supported by higher baseline levels of interleukin 1β release in P2Y 13 KO mice.…”

Section: Introductionmentioning

confidence: 95%

“…In the healthy brain, microglia are highly motile ramified cells that constantly extend and retract their processes to survey the CNS tissue (Davalos et al, ; Nimmerjahn, Kirchhoff, & Helmchen, ). We recently showed that this mode of microglial motility is regulated by the membrane potential generated by tonic activity of the two‐pore domain potassium channel THIK‐1 (Madry, Arancibia‐Cárcamo, et al, ; Madry, Kyrargyri, et al, ). Under pathological conditions, such as brain tissue damage, disease or infection, microglia become activated, upregulating surface receptors such as MHCII and A 2A , while their morphology becomes less ramified, with fewer, shorter processes, and larger somata (Kreutzberg, ; Orr, Orr, Li, Gross, & Traynelis, ).…”

Section: Introductionmentioning

confidence: 99%

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P2Y₁₃ receptors regulate microglial morphology, surveillance, and resting levels of interleukin 1β release

Kyrargyri

Madry

Rifat

et al. 2019

Glia

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Microglia sense their environment using an array of membrane receptors. While P2Y12 receptors are known to play a key role in targeting directed motility of microglial processes to sites of damage where ATP/ADP is released, little is known about the role of P2Y13, which transcriptome data suggest is the second most expressed neurotransmitter receptor in microglia. We show that, in patch‐clamp recordings in acute brain slices from mice lacking P2Y13 receptors, the THIK‐1 K+ current density evoked by ADP activating P2Y12 receptors was increased by ~50%. This increase suggested that the P2Y12‐dependent chemotaxis response should be potentiated; however, the time needed for P2Y12‐mediated convergence of microglial processes onto an ADP‐filled pipette or to a laser ablation was longer in the P2Y13 KO. Anatomical analysis showed that the density of microglia was unchanged, but that they were less ramified with a shorter process length in the P2Y13 KO. Thus, chemotactic processes had to grow further and so arrived later at the target, and brain surveillance was reduced by ~30% in the knock‐out. Blocking P2Y12 receptors in brain slices from P2Y13 KO mice did not affect surveillance, demonstrating that tonic activation of these high‐affinity receptors is not needed for surveillance. Strikingly, baseline interleukin‐1β release was increased fivefold while release evoked by LPS and ATP was not affected in the P2Y13 KO, and microglia in intact P2Y13 KO brains were not detectably activated. Thus, P2Y13 receptors play a role different from that of their close relative P2Y12 in regulating microglial morphology and function.

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Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1

Cited by 336 publications

References 65 publications

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

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

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

P2Y₁₃ receptors regulate microglial morphology, surveillance, and resting levels of interleukin 1β release

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Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1

Cited by 336 publications

References 65 publications

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

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

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

P2Y13 receptors regulate microglial morphology, surveillance, and resting levels of interleukin 1β release

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P2Y₁₃ receptors regulate microglial morphology, surveillance, and resting levels of interleukin 1β release