TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain

Kobayashi, Masaaki; Konishi, Hiroyuki; Sayo, Akira; Takai, Toshiyuki; Kiyama, Hiroshi

doi:10.1523/jneurosci.1238-16.2016

Cited by 106 publications

(117 citation statements)

References 62 publications

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“…4) The time course of the PNIinduced SDH microgliosis in mice was revealed to be that microglia number increased from day 3, peaked at 1 week and declined later, which is almost similar to the temporal pattern of microgliosis reported in previous studies. 11,25,26) Under such conditions, we clearly showed that a proliferation burst of SDH microglia occurred during the early phase (the first 3 d after PNI) but not during the later phase (at least until 2 weeks post-PNI). The early phase proliferation is consistent with several previous papers, 11,13) but the later phase is controversial.…”

Section: Discussionmentioning

confidence: 82%

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: 82%

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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“…However, it is noteworthy that even in naive animals, GFP+ cells were found in the spinal cord, which suggested that the leukocyte infiltration was independent of SNI induction (Fig. B), most likely caused by the irradiation as an experimental artifact …”

Section: Resultsmentioning

confidence: 97%

“…More recently, it was shown that the infiltration of circulating cells in the spinal cord of mice after peripheral nerve injury can vary according to the intensity of irradiation applied to the animal, showing that the doses of radiation used in previous work could be causing side effects (e.g., breaking BBB) . On the other hand, there is also evidence showing that peripheral nerve injury does not induce leukocyte infiltration in the spinal cord …”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Guimarães

Davoli‐Ferreira

Fonseca

et al. 2019

Journal of Leukocyte Biology

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The development of neuropathic pain after peripheral nerve injury involves neuroimmune–glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2‐deficient mice. These results suggest that blood‐circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2‐expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.

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“…The microglial manipulations including ramification are sought to bring about therapeutic benefits for patients who suffer from neuropathic pain (Kobayashi, Konishi, Sayo, Takai, & Kiyama, ; Tsuda et al, ), neurodegenerative diseases (Boillee et al, ), and even mental disorders (Bayer, Buslei, Havas, & Falkai, ; Morgan et al, ; Yasui et al, ), although some attempts have been made to induce ramified shapes in microglia in vitro (Rosenstiel et al, ). To induce a ramified shape in primary cultured microglia, the stromal cell‐derived factor (SDF)−1a, CSF‐1 (M‐CSF), and a combination of GM‐CSF/IL‐34 were previously examined (Muessel et al, ; Neubrand et al, ; Ohgidani et al, ).…”

Section: Discussionmentioning

confidence: 99%

Phospholipid localization implies microglial morphology and function via Cdc42 in vitro

Tokizane

Konishi

Makide

et al. 2017

Glia

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Under a quiescent state, microglia exhibit a ramified shape, rather than the amoeboid-like morphology following injury or inflammation. The manipulation of microglial morphology in vitro has not been very successful, which has impeded the progress of microglial studies. We demonstrate that lysophosphatidylserine (LysoPS), a kind of lysophospholipids, rapidly and substantially alters the morphology of primary cultured microglia to an in vivo-like ramified shape in a receptor independent manner. This mechanism is mediated by Cdc42 activity. LysoPS is incorporated into the plasma membrane and converted to phosphatidylserine (PS) via the Lands' cycle. The accumulated PS on the membrane recruits Cdc42. Both Cdc42 and PS colocalize predominantly in primary and secondary processes, but not in peripheral branches or tips of microglia. Along with the morphological changes LysoPS suppresses inflammatory cytokine production and NF-kB activity. The present study provides a tool to manipulate a microglial phenotype from an amoeboid to a fully ramified in vitro, which certainly contributes to studies exploring microglial physiology and pathology.

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TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain

Cited by 106 publications

References 62 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

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Phospholipid localization implies microglial morphology and function via Cdc42 in vitro

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