Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury

Peng, Jinrong; Gu, Nan; Zhou, Lijun; Eyo, Ukpong B.; Murugan, Madhuvika; Gan, Wen Biao; Wu, Long Jun

doi:10.1038/ncomms12029

Cited by 261 publications

(287 citation statements)

References 54 publications

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“…Typically, clodronate liposomes were used to deplete various kinds of macrophage/monocyte [22,23], such as primitive macrophages [24] microglia [25], Kupffer cells [26], alveolar macrophage [27], monocytes [25], tumor-associated macrophages [28,29]. Therefore, in this study, we packaged Fasudil in liposomes to realize the specific 4 targeting to macrophages/monocytes.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

et al. 2018

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Macrophages play essential roles in the generation and resolution of inflammation. Ischemia-reperfusion injury (IRI) triggers a systemic inflammatory response and leads to cellular injury and organ failure.During surgical procedures of the liver, such as hepatic resection and liver transplantation, IRI leads to the dysfunction of the liver. Rho-associated protein kinase (ROCK) inhibitors were reported protecting the liver from IRI. However, the systematic administration of ROCK inhibitors causes severe hypotension.Here, using Fasudil carried liposomes, we specifically inhibited the ROCK-II expression in Kupffer cells and blood monocytes. Through this macrophage/monocyte specific treatment of Fasudil, we successfully protected the liver from IRI by shifting Kupffer cells/monocytes from M1/classical to M2/patrolling phenotype in the liver and peripheral blood. Our finding provides novel insights into the macrophage/monocyte-specific drug delivery and the treatment of liver IRI.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

et al. 2018

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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: 87%

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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“…ATP is released by injured dorsal horn neurons [90], whereupon microglial purinergic receptors are activated, leading to microglial proliferation and neuropathic pain [91-94, 95•]. The apparent reduction in the importance of microglial activity in the later stages of neuropathic pain models has led to the suggestion that microgliosis and inflammatory mediator production may be most important in the initiation of hypersensitivity and promoting the transition to chronic pain [96].…”

Section: Changes In the Spinal Cordmentioning

confidence: 99%

Neuropathic Pain: Central vs. Peripheral Mechanisms

Meacham

Shepherd

Mohapatra

et al. 2017

Curr Pain Headache Rep

329

203

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Recent preclinical studies in pNP support and provide key details concerning the role of multiple mechanisms leading to fiber hyperexcitability and sustained electrical discharge to the CNS. In studies regarding central mechanisms, new preclinical evidence includes the mapping of novel inhibitory circuitry and identification of the molecular basis of microglia-neuron crosstalk. Recent clinical evidence demonstrates the essential role of peripheral mechanisms, mostly via studies that block the initially damaged peripheral circuitry. Clinical central mechanism studies use imaging to identify potentially self-sustaining infra-slow CNS oscillatory activity that may be unique to pNP patients. While new preclinical evidence supports and expands upon the key role of central mechanisms in neuropathic pain, clinical evidence for an autonomous central mechanism remains relatively limited. Recent findings from both preclinical and clinical studies recapitulate the critical contribution of peripheral input to maintenance of neuropathic pain. Further clinical investigations on the possibility of standalone central contributions to pNP may be assisted by a reconsideration of the agreed terms or criteria for diagnosing the presence of central sensitization in humans.

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Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury

Cited by 261 publications

References 54 publications

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

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

Neuropathic Pain: Central vs. Peripheral Mechanisms

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