Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain Hypersensitivity

Griffin, Robert S.; Costigan, Michael; Brenner, Gary J.; Eddie, Chi Him; Scholz, Joachim; Moss, Andrew; Allchorne, Andrew; Stahl, Gregory L.; Woolf, Clifford J.

doi:10.1523/jneurosci.2018-07.2007

Cited by 218 publications

(250 citation statements)

References 75 publications

(81 reference statements)

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“…In fact, following peripheral nerve injury, reactive microglia engulf myelinated axons with their processes in the spinal dorsal horn in a manner that is dependent on P2Y 12 R signals [27]. Furthermore, microglial chemotaxis-related genes are upregulated in the spinal cord and are required for the generation of neuropathic pain [28][29][30][31]. However, whether microglial motility itself correlates with the degree of pain hypersensitivity remains unclear.…”

Section: Discussionmentioning

confidence: 99%

IRF8 is a transcriptional determinant for microglial motility

Masuda

Nishimoto

Tomiyama

et al. 2014

Purinergic Signalling

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Microglia, the resident immune cells of the central nervous system, are constitutively mobile cells that undergo rapid directional movement toward sites of tissue disruption. However, transcriptional regulatory mechanisms of microglial motility remain unknown. In the present study, we show that interferon regulatory factor-8 (IRF8) regulates microglial motility. We found that ATP and complement component, C5a, induced chemotaxis of IRF8 wild-type microglia. However, these responses were markedly suppressed in microglia lacking IRF8 (Irf8 −/− ). In a consistent manner, phosphorylation of Akt (which plays a crucial role in ATP-induced chemotaxis) was abolished in Irf8 −/− microglia. Real-time polymerase chain reaction analysis revealed that motility-related microglial genes such as P2Y 12 receptor were significantly suppressed in Irf8 −/− microglia. Furthermore, Irf8 −/− microglia exhibited a differential expression pattern of nucleotidedegrading enzymes compared with their wild-type counterparts. Overall, our findings suggest that IRF8 may regulate microglial motility via the control of microglial gene expression.

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Section: Discussionmentioning

confidence: 99%

IRF8 is a transcriptional determinant for microglial motility

Masuda

Nishimoto

Tomiyama

et al. 2014

Purinergic Signalling

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“…Activation of complement cascade in spinal microglia also plays a role in neuropathic pain (Griffin et al, 2007). A recent microarray study shows that the most regulated transcripts among different nerve injury models are related to complement components (e.g., C1q, C3, and C4).…”

Section: The Role Of Microglia In Pain Controlmentioning

confidence: 99%

“…A recent microarray study shows that the most regulated transcripts among different nerve injury models are related to complement components (e.g., C1q, C3, and C4). In addition, the terminal complement component C5 and its receptor C5aR are upregulated in spinal microglia after peripheral nerve injury and are required for neuropathic pain sensitivity (Griffin et al, 2007).…”

Section: The Role Of Microglia In Pain Controlmentioning

confidence: 99%

Do glial cells control pain?

Wen²,

et al. 2007

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Management of chronic pain is a real challenge, and current treatments focusing on blocking neurotransmission in the pain pathway have only resulted in limited success. Activation of glia cells has been widely implicated in neuroinflammation in the central nervous system, leading to neruodegeneration in many disease conditions such as Alzheimer's and multiple sclerosis. The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-α and interleukin-1β can not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions. Pain can also be potentiated by growth factors such as BDNF and bFGF that are produced by glia to protect neurons. Thus, glia cells can powerfully control pain when they are activated to produce various pain mediators. We will review accumulating evidence supporting an important role of microglia cells in the spinal cord for pain control under injury conditions (e.g. nerve injury). We will also discuss possible signaling mechanisms in particular MAP kinase pathways that are critical for glia control of pain. Investigating signaling mechanisms in microglia may lead to more effective management of devastating chronic pain.

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“…By responding to extracellular stimuli such as ATP, the activated microglia evoke various cellular responses such as production and release of bioactive factors, including cytokines and neurotrophic factors (18,19). Importantly, pharmacological, molecular, and genetic manipulations of the function or expression of these microglial molecules substantially influence nerve injury-induced pain behaviors (12)(13)(14)(15)(16)(20)(21)(22) and the hyperexcitability of the dorsal horn pain pathway (23,24). Therefore, spinal microglia activated after nerve injury critically contribute to the pathologically enhanced pain processing in the dorsal horn that underlies neuropathic pain (5-9).…”

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confidence: 99%

IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain

Tsuda

Masuda

Kitano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

253

230

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Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. Here we show that in naive animals spinal microglia express a receptor for the cytokine IFN-␥ (IFN-␥R) in a cell-type-specific manner and that stimulating this receptor converts microglia into activated cells and produces a long-lasting pain hypersensitivity evoked by innocuous stimuli (tactile allodynia, a hallmark symptom of neuropathic pain). Conversely, ablating IFN-␥R severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-␥-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X 4 receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-␥R-dependent microglial and behavioral alterations. These results suggest that IFN-␥R is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.allodynia ͉ cytokine ͉ glia ͉ Lyn tyrosine kinase ͉ purinergic receptor

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Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain Hypersensitivity

Cited by 218 publications

References 75 publications

IRF8 is a transcriptional determinant for microglial motility

IRF8 is a transcriptional determinant for microglial motility

Do glial cells control pain?

IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain

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