TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States

Batti, Laura; Sundukova, Mayya; Murana, Emanuele; Pimpinella, Sofia; Reis, Fernanda de Castro; Pagani, Francesca; Wang, Hong; Pellegrino, Eloisa; Perlas, Emerald; Angelantonio, Silvia Di; Ragozzino, Davide; Heppenstall, Paul A.

doi:10.1016/j.celrep.2016.05.039

Cited by 51 publications

(53 citation statements)

References 49 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whether the alteration in the process morphology of SDH microglia contributes to subsequent proliferation and neuropathic pain induction remains unknown. 4) Given that PNI-induced pain hypersensitivity is blunted in mice lacking a molecule (P2Y12 receptor or transmembrane protein 16F) that regulates the shape of microglial processes, 29,30) it is possible that the first morphological change in SDH microglia by PNI may also have a role in subsequent microgliosis and neuropathic pain.…”

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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Additionally, spinally administered PPAR-γ agonist attenuated hypersensitivity in male rats 49 , contrasting the predominant role of PPAR-γ in female mice 44 . Furthermore, other studies found no differences between female and male mice in microglia-mediated hypersensitivity 17, 32 . Future research will need to clarify whether the sex-related role of glia is restricted to selected mechanisms or models of neuropathic pain and how these findings are relevant to clinical pain.…”

Section: Glia and Sex Differencesmentioning

confidence: 83%

“…( B ) Neuro-glial mechanisms in the dorsal horn spinal cord (dashed box in A): (i) CSF1 released from injured DRG neurons activates CSF1 receptor (CSF1R) in microglia 15, 16 . (ii) TMEM16F in microglia mediates their phagocytosis of GABAergic-interneuron terminals 17 . (iii) Whether monocytes infiltrate spinal cord and their relative role versus resident microglia are still unclear 22, 26, 28, 29, 32 .…”

Section: Microgliamentioning

confidence: 99%

“…New work proposes that a Ca 2+ -dependent channel, TMEM16F, in microglia mediates their phagocytic activity, which leads to the shortening of GABAergic interneuron terminals, subsequent loss of GABA-mediated inhibitory transmission, and neuropathic pain 17 ( Figure 1Bii). The concept is in line with recently postulated loss of synaptic contacts between spinal parvalbumin-expressing inhibitory interneurons and excitatory interneurons leading to their disinhibition 18 , and this represents an alternative mechanism to the controversial apoptosis of inhibitory interneurons 19, 20 .…”

Section: Microgliamentioning

confidence: 99%

“…Selective depletion of microglial TMEM16F diminished microglia-mediated phagocytosis, preserved neuronal GABA immunoreactivity, and abolished hypersensitivity following sciatic nerve injury (ScNI) in mice. Thus, microglia phagocytic activity may contribute to neuropathic pain 17 .…”

Section: Microgliamentioning

confidence: 99%

See 2 more Smart Citations

Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics

Machelska

Celik

2016

F1000Res

View full text Add to dashboard Cite

Neuropathic pain results from diseases or trauma affecting the nervous system. This pain can be devastating and is poorly controlled. The pathophysiology is complex, and it is essential to understand the underlying mechanisms in order to identify the relevant targets for therapeutic intervention. In this article, we focus on the recent research investigating neuro-immune communication and epigenetic processes, which gain particular attention in the context of neuropathic pain. Specifically, we analyze the role of glial cells, including microglia, astrocytes, and oligodendrocytes, in the modulation of the central nervous system inflammation triggered by neuropathy. Considering epigenetics, we address DNA methylation, histone modifications, and the non-coding RNAs in the regulation of ion channels, G-protein-coupled receptors, and transmitters following neuronal damage. The goal was not only to highlight the emerging concepts but also to discuss controversies, methodological complications, and intriguing opinions.

show abstract

ProMoIJ: A new tool for automatic three‐dimensional analysis of microglial process motility

Paris

Savage

Escobar

et al. 2017

Glia

View full text Add to dashboard Cite

Microglia, the immune cells of the central nervous system, continuously survey the brain to detect alterations and maintain tissue homeostasis. The motility of microglial processes is indicative of their surveying capacity in normal and pathological conditions. The gold standard technique to study motility involves the use of two-photon microscopy to obtain time-lapse images from brain slices or the cortex of living animals. This technique generates four dimensionally-coded images which are analyzed manually using time-consuming, non-standardized protocols. Microglial process motility analysis is frequently performed using Z-stack projections with the consequent loss of three-dimensional (3D) information. To overcome these limitations, we developed ProMoIJ, a pack of ImageJ macros that perform automatic motility analysis of cellular processes in 3D. The main core of ProMoIJ is formed by two macros that assist the selection of processes, automatically reconstruct their 3D skeleton, and analyze their motility (process and tip velocity). Our results show that ProMoIJ presents several key advantages compared with conventional manual analysis: (1) reduces the time required for analysis, (2) is less sensitive to experimenter bias, and (3) is more robust to varying numbers of processes analyzed. In addition, we used ProMoIJ to demonstrate that commonly performed 2D analysis underestimates microglial process motility, to reveal that only cells adjacent to a laser injured area extend their processes toward the lesion site, and to demonstrate that systemic inflammation reduces microglial process motility. ProMoIJ is a novel, open-source, freely-available tool which standardizes and accelerates the time-consuming labor of 3D analysis of microglial process motility.

show abstract

TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States

Cited by 51 publications

References 49 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

Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics

ProMoIJ: A new tool for automatic three‐dimensional analysis of microglial process motility

Contact Info

Product

Resources

About