Phosphorylation of ezrin/radixin/moesin (ERM) protein in spinal microglia following peripheral nerve injury and lysophosphatidic acid administration

Kashimoto, Ryosuke; Yamanaka, Hiroki; Kobayashi, Kimiko; Okubo, Masamichi; Yagi, Hideshi; Mimura, Osamu; Noguchi, Koichi

doi:10.1002/glia.22436

Cited by 7 publications

(3 citation statements)

References 60 publications

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“…injection of LPA mimicked the behavioral changes, demyelination and several biochemical changes caused by nerve injury [20,23,25]. This unique approach to study neuropathic pain and its mechanisms was further confirmed by other groups [26-28]. Emerging findings were observed with the studies of biosynthesis of LPA in the spinal cord or dorsal root in the neuropathic pain model.…”

Section: Introductionmentioning

confidence: 76%

An LPA Species (18:1 LPA) Plays Key Roles in the Self-Amplification of Spinal LPA Production in the Peripheral Neuropathic Pain Model

Nagai

Chun

et al. 2013

Mol Pain

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BackgroundWe previously reported that nerve injury-induced neuropathic pain is initiated by newly produced lysophosphatidic acid (LPA).ResultsIn this study, we developed a quantitative mass spectrometry for detecting LPA species by using Phos-tag. Following nerve injury, the levels of 18:1, 16:0 and 18:0 LPA in the spinal dorsal horn significantly increased at 3 h and declined at 6 h. Among them, 18:1 LPA level was the most abundant. In the same preparation, there were significant elevations in the activities of cytosolic phospholipase A2 (cPLA2) and calcium-independent phospholipase A2 (iPLA2), key enzymes for LPA synthesis, at 1 h, while there was no significant change in phospholipase A1 activity. Pharmacological studies revealed that NMDA and neurokinin 1 receptors, cPLA2, iPLA2 and microglial activation, as well as LPA1 and LPA3 receptors were all involved in the nerve injury-induced LPA production, and underlying cPLA2 and iPLA2 activations. In the cells expressing LPA1 or LPA3 receptor, the receptor-mediated calcium mobilization was most potent with 18:1 LPA, compared with 16:0 or 18:0 LPA. Moreover, the intrathecal injection of 18:1 LPA, but not 16:0 or 18:0 LPA, caused a spinal LPA production and neuropathic pain-like behavior.ConclusionThese results suggest that 18:1 LPA is the predominant ligand responsible for LPA1 and LPA3 receptors-mediated amplification of LPA production through microglial activation.

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Section: Introductionmentioning

confidence: 76%

An LPA Species (18:1 LPA) Plays Key Roles in the Self-Amplification of Spinal LPA Production in the Peripheral Neuropathic Pain Model

Nagai

Chun

et al. 2013

Mol Pain

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“…This protein belongs to the ezrin-radixin-moesin (ERM) family of proteins, which plays structural and regulatory roles in the rearrangement of plasma membrane flexibility and protrusions through interaction with cortical actin filaments and the plasma membrane (Pore and Gupta 2015). Since it has been reported that moesin is expressed in microglia/macrophages (Moon, Kim et al 2011, Kashimoto, Yamanaka et al 2013, and microglia activation is one characteristic feature of early cuprizone lesions, we focused on this particular ERM-protein.…”

Section: Resultsmentioning

confidence: 99%

“…Expression and/or activation of moesin in microglia is less well appreciated, but microglia in the spinal cord were found to express moesin in a model of peripheral nerve injury (Kashimoto, Yamanaka et al 2013). Furthermore, it has been shown that microglia express moesin in cryogenic traumatic brain injury of the mouse cortex (Moon, Kim et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocyte degeneration and concomitant microglia activation directs peripheral immune cells into the forebrain

Chrzanowski

Bhattarai

Scheld

et al. 2019

Neurochemistry International

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Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently showed that encephalitogenic lymphocytes are recruited to the sites of active demyelination induced by cuprizone. Here, we investigated whether cuprizoneinduced oligodendrocyte and myelin pathology is sufficient to trigger peripheral immune cell recruitment into the forebrain. We show that early cuprizone-induced white matter lesions display a striking similarity to early MS lesions, i.e., oligodendrocyte degeneration, microglia activation and absence of severe lymphocyte infiltration. Such early cuprizone lesions are sufficient to trigger peripheral immune cell recruitment secondary to subsequent EAE (experimental autoimmune encephalomyelitis) induction. The lesions are characterized by discontinuation of the perivascular glia limitans, focal axonal damage, and perivascular astrocyte pathology. Time course studies showed that the severity of cuprizone-induced lesions positively correlates with the extent of peripheral immune cell recruitment. Furthermore, results of genome-wide array analyses suggest that moesin is integral for early microglia activation in cuprizone and MS lesions. This study underpins the significance of brainintrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation.

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Interleukin-1β Plays Key Roles in LPA-Induced Amplification of LPA Production in Neuropathic Pain Model

Yano

Nagai

et al. 2013

Cell Mol Neurobiol

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Lysophosphatidic acid (LPA) is a bioactive lipid mediator that exerts a wide range of biological actions. In recent decades, LPA has been demonstrated as an important initiator of neuropathic pain based on the mechanisms of LPA-induced feed-forward LPA amplification. In this study, we examined the possible involvement of interleukin (IL)-1β in such LPA production. Intrathecal (i.t.) LPA injection rapidly increased the expression of IL-1β mRNA in the spinal dorsal horn as early as 0.5 h after injection, and the level reached peak at 2 h. Through a developed quantitative mass spectrometry for detecting LPA species, the elevated levels of 18:1, 16:0, and 18:0 LPA in the spinal dorsal horn were observed at 3 h after 18:1 LPA injection and this elevation was completely blocked by the pretreatment of IL-1β-neutralizing antibody. Moreover, enzyme assay experiments showed that LPA (i.t.) significantly activated calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) in the spinal dorsal horn at 1 and 2 h, respectively, and these biochemical changes were also significantly inhibited by IL-1β-neutralizing antibody. Similarly, IL-1β-neutralizing antibody reversed LPA-induced neuropathic pain-like behavior. These findings suggest that the early release of IL-1β is involved in LPA-induced amplification of LPA production, which underlies the initial mechanisms of LPA-induced neuropathic pain.

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Phosphorylation of ezrin/radixin/moesin (ERM) protein in spinal microglia following peripheral nerve injury and lysophosphatidic acid administration

Cited by 7 publications

References 60 publications

An LPA Species (18:1 LPA) Plays Key Roles in the Self-Amplification of Spinal LPA Production in the Peripheral Neuropathic Pain Model

An LPA Species (18:1 LPA) Plays Key Roles in the Self-Amplification of Spinal LPA Production in the Peripheral Neuropathic Pain Model

Oligodendrocyte degeneration and concomitant microglia activation directs peripheral immune cells into the forebrain

Interleukin-1β Plays Key Roles in LPA-Induced Amplification of LPA Production in Neuropathic Pain Model

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