JNK-Induced MCP-1 Production in Spinal Cord Astrocytes Contributes to Central Sensitization and Neuropathic Pain

Gao, Yong‐Jing; Zhang, Ling; Samad, Omar Abdel; Suter, Marc R; Kawasaki, Yuki; Xu, Zhen-Zhong; Park, Jong Yeon; Lind, Anne-Li; Ma, Qiufu; Ji, Ru-Rong

doi:10.1523/jneurosci.3623-08.2009

Cited by 513 publications

(684 citation statements)

References 76 publications

(134 reference statements)

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“…6b), suggesting that lack of presenilins affects TNF␣-mediated CXCL1 chemokine production. Interestingly, and consistent with our reported defect in JNK MAPK activation in PS DKO MEFs, it has been reported that CXCL1 production is dependent upon TNF␣-stimulated JNK MAPK activation (72)(73)(74). To further validate this observation, we used wild type and the partial knock-out Psen1 ϩ/Ϫ / Psen2 Ϫ/Ϫ murine model, which have the maximum reduction in presenilin expression that is compatible with viability.…”

Section: Presenilin Deficiency Is Associated With Enhanced Formationsupporting

confidence: 78%

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

Chhibber‐Goel

Coleman-Vaughan

Agrawal

et al. 2016

Journal of Biological Chemistry

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The ␥-secretase protease and associated regulated intramembrane proteolysis play an important role in controlling receptormediated intracellular signaling events, which have a central role in Alzheimer disease, cancer progression, and immune surveillance. An increasing number of ␥-secretase substrates have a role in cytokine signaling, including the IL-6 receptor, IL-1 receptor type I, and IL-1 receptor type II. In this study, we show that following TNF-converting enzyme-mediated ectodomain shedding of TNF type I receptor (TNFR1), the membranebound TNFR1 C-terminal fragment is subsequently cleaved by ␥-secretase to generate a cytosolic TNFR1 intracellular domain. We also show that clathrin-mediated internalization of TNFR1 C-terminal fragment is a prerequisite for efficient ␥-secretase cleavage of TNFR1. Furthermore, using in vitro and in vivo model systems, we show that in the absence of presenilin expression and ␥-secretase activity, TNF-mediated JNK activation was prevented, assembly of the TNFR1 pro-apoptotic complex II was reduced, and TNF-induced apoptosis was inhibited. These observations demonstrate that TNFR1 is a ␥-secretase substrate and suggest that ␥-secretase cleavage of TNFR1 represents a new layer of regulation that links the presenilins and the ␥-secretase protease to pro-inflammatory cytokine signaling.The biological activities of the tumor necrosis factor-␣ (TNF) pro-inflammatory cytokine are resolved by two distinct cell surface receptors, TNFR1 3 and TNFR2, which elicit a diversity of cellular responses, such as inflammation, cell proliferation, cell differentiation, and initiation of apoptosis (1-10). TNFR1 initiates either pro-inflammatory or pro-apoptotic signaling through the selective recruitment of intracellular adaptor and effector proteins (1,3,6,7,11). Ligand binding and trimerization of TNFR1 enables the recruitment of TNFR1-associated death domain protein (TRADD) (12, 13), which functions as a scaffold enabling the recruitment of receptorinteracting protein kinase 1 (RIPK1) (14 -16), TNF receptorassociated factor 2 (TRAF2) or TRAF5 (12), and the cellular inhibitor of apoptosis proteins (cIAPs) cIAP1 and cIAP2 (11), which collectively form a signaling composite called complex I (17-19). The resulting lysine 63-linked polyubiquitination of RIPK1 by TRAF2 and the cIAPs (20 -24) enables an interaction with the IB kinase complex that mediates the phosphorylation and degradation of IB-inhibitory proteins and activation of the transcription factor NF-B to promote non-apoptotic signaling pathways (25-27). NF-B also increases expression of anti-apoptotic genes, including cIAPs and FLICE inhibitory protein (c-FLIP), further ensuring a non-apoptotic signaling pathway.The importance of receptor internalization as a regulatory mechanism for the segregation and divergence of intracellular signaling pathways is highlighted by studies on internalization of TNFR1 and TNFR2, the Fas receptor (FasR/CD95), IL-1 receptor I, Toll-like receptor 4, and TRAIL receptors (18, 28 -33). The current favored m...

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Section: Presenilin Deficiency Is Associated With Enhanced Formationsupporting

confidence: 78%

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

Chhibber‐Goel

Coleman-Vaughan

Agrawal

et al. 2016

Journal of Biological Chemistry

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“…In addition, although our findings are consistent with a role for MCP-1/CCR2 signaling within the DRG, it is also possible that CCR2 signaling is important in the spinal cord. MCP-1/CCR2 may be acting in the dorsal horn, as has been suggested (26,35,36), further contributing to the observed phenotype in the Ccr2-null mice.…”

Section: Discussionmentioning

confidence: 78%

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Miller

Tran

Das

et al. 2012

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

242

281

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Osteoarthritis is one of the leading causes of chronic pain, but almost nothing is known about the mechanisms and molecules that mediate osteoarthritis-associated joint pain. Consequently, treatment options remain inadequate and joint replacement is often inevitable. Here, we use a surgical mouse model that captures the long-term progression of knee osteoarthritis to longitudinally assess pain-related behaviors and concomitant changes in the innervating dorsal root ganglia (DRG). We demonstrate that monocyte chemoattractant protein (MCP)-1 (CCL2) and its high-affinity receptor, chemokine (C-C motif) receptor 2 (CCR2), are central to the development of pain associated with knee osteoarthritis. After destabilization of the medial meniscus, mice developed early-onset secondary mechanical allodynia that was maintained for 16 wk. MCP-1 and CCR2 mRNA, protein, and signaling activity were temporarily up-regulated in the innervating DRG at 8 wk after surgery. This result correlated with the presentation of movement-provoked pain behaviors, which were maintained up to 16 wk. Mice that lack Ccr2 also developed mechanical allodynia, but this started to resolve from 8 wk onwards. Despite severe allodynia and structural knee joint damage equal to wild-type mice, Ccr2-null mice did not develop movement-provoked pain behaviors at 8 wk. In wild-type mice, macrophages infiltrated the DRG by 8 wk and this was maintained through 16 wk after surgery. In contrast, macrophage infiltration was not observed in Ccr2-null mice. These observations suggest a key role for the MCP-1/CCR2 pathway in establishing osteoarthritis pain.O steoarthritis is the most common joint disorder and is one of the leading causes of chronic pain (1, 2). Osteoarthritis commonly affects knees, hips, and hands and is characterized by radiographic changes (primarily joint space narrowing, subchondral bone sclerosis, and osteophytes) accompanied by clinical symptoms, most prominently pain. Treatments that alter the progression of the structural damage in the joint are not yet available. Options for treating the pain include nonsteroidal anti-inflammatory drugs, steroids, and viscosupplementation, but analgesia is often inadequate, and uncontrolled pain is the number one reason why people with osteoarthritis undergo joint-replacement surgery (3). Despite the enormous health and economic burden of osteoarthritis and associated pain (4), very few studies have examined the molecular pathways that mediate osteoarthritis pain. As in all types of chronic pain, osteoarthritis pain is the dynamic result of a complex interaction between local tissue damage and inflammation, peripheral and central sensitization, and the brain (5-7). Joint pain associated with osteoarthritis, however, has unique clinical features that provide insight into the mechanisms that cause it. First, joint pain has a strong mechanical component: it is typically triggered by specific activities (for example, climbing stairs elicits knee pain) and is relieved by rest. As structural joint disease advance...

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“…Without a more complete understanding of the stimulus-dependent phenotypic changes of spinal microglia to PNI, attempting to inhibit their function may have deleterious as well as beneficial effects. Finally, evidence is accumulating for astrocytic involvement in spinal modulation of neuropathic pain states [34][35][36] although the specific signalling pathways to neurons and how they interact with microglia/ disinhibition remain to be established. The current hypothesis, combining new evidence that builds on the original model.…”

Section: Resultsmentioning

confidence: 99%

Microglia–neuronal signalling in neuropathic pain hypersensitivity 2.0

Beggs¹,

Salter²

2010

Current Opinion in Neurobiology

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Microglia are increasingly recognized as critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. The core signalling pathway is through P2X4 purinergic receptors on the microglia which, via the release brain derived neurotrophic factor, cause disinhibition of nociceptive dorsal horn neurons by raising intracellular chloride levels. This disinhibition works in synergy with enhanced excitatory synaptic transmission in the dorsal horn to transform the output of the nociceptive network. There is increased discharge output, unmasking of responses to innocuous peripheral inputs, and spontaneous activity in neurons that otherwise only signal nociception. Together the changes caused by microglia-neuron signalling may account for the main symptoms neuropathic pain in humans.

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JNK-Induced MCP-1 Production in Spinal Cord Astrocytes Contributes to Central Sensitization and Neuropathic Pain

Cited by 513 publications

References 76 publications

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Microglia–neuronal signalling in neuropathic pain hypersensitivity 2.0

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