Visualization of Chemokine Receptor Activation in Transgenic Mice Reveals Peripheral Activation of CCR2 Receptors in States of Neuropathic Pain

Jung, Hosung; Bhangoo, Sonia K.; Banisadr, Ghazal; Freitag, Caroline M.; Ren, Dongjun; White, Fletcher A.; Miller, Richard J.

doi:10.1523/jneurosci.0485-09.2009

Cited by 123 publications

(154 citation statements)

References 54 publications

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“…It is interesting to note that the source of MCP-1 in these experiments appears to be the DRG neurons themselves. This up-regulated expression of both MCP-1 and CCR2 by DRG neurons is consistent with our previous findings (30,34) in other models of chronic pain, and suggests that CCR2 signaling within the DRG may play an important role in the genesis of nociceptor hyperexcitability.…”

Section: Discussionsupporting

confidence: 92%

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CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Miller

Tran

Das

et al. 2012

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

238

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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Section: Discussionsupporting

confidence: 92%

“…This process has been demonstrated on cultured (18) and previously injured adult DRG sensory neurons (27,(29)(30)(31)(32). In addition, chemokines are of central importance in the recruitment of leukocytes.…”

Section: Discussionmentioning

confidence: 83%

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Miller

Tran

Das

et al. 2012

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

238

281

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“…To identify CCL2-expressing cells in the brain, CCL2::RFP transcriptional reporter mice were subjected to saline solution or KA (30 mg/kg) to induce SE and killed 1 or 3 d later. Use of this transcriptional reporter line allows for intracellular labeling and identification of cells expressing Ccl2 mRNA (31). Notably, there was little staining for CCL2::RFP in the hippocampus of saline solution-treated mice.…”

Section: Resultsmentioning

confidence: 99%

“…CCL2::mRFP transcriptional reporter mice express mRFP from the CCL2 promoter. The reporter gene was introduced into the mouse genome by using bacterial artificial chromosome technologies (31). Female CCL2::mRFP mice maintained on the Jackson Laboratory B6 background were bred to inbred FVB mice to generate F1 hybrid B6.FVB-CCL2::mRFP.…”

Section: Methodsmentioning

confidence: 99%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

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

279

291

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The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2 + ) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3 + T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2 + monocytes could represent a viable method for alleviating the deleterious consequences of SE. myeloid cell heterogeneity | epileptogenesis | neuroprotection | seizure | microgliosis S tatus epilepticus (SE) is a serious medical emergency that triggers a series of cellular and molecular events that can result in the development of epilepsy, a chronic neurological disorder characterized by a persistently lowered seizure threshold (1). The early consequences of SE in rodents include a robust neuroinflammatory response, selective neuronal degeneration, and transient opening of the blood-brain barrier (BBB), leading to later cognitive decline. Although the neuroinflammatory features of SE in man are less well known, extravasation of albumin into the brain was observed for patients who died in SE (2), elevated cerebrospinal fluid levels of the cytokines IL-6, IL-8, and CXCL10 are typically found in patients with refractory SE compared with patients with other inflammatory neurologic disorders (3), and intense gliosis (both astrocytes and microglia) was observed in the temporal cortex of a patient with new-onset focal seizures that progressed to refractory SE (4). These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflamma...

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“…However, the effect was more potent in MCP1 -/-mice than in wild-type mice. It has been shown that MCP1 binds to and reduces membrane 1491 Truncated MCP1 disrupts the blood-brain barrier CCR2 levels (probably through endocytosis) (Jung et al, 2009;Yao and Tsirka, 2010). The dramatic change observed in MCP1 -/-mice could be due to higher membrane CCR2 density, as in the absence of MCP1 there would be no recycling of CCR2 off the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

Yao

Tsirka

2011

Journal of Cell Science

102

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SummaryPrevious studies have shown that plasmin cleaves monocyte chemoattractant protein 1 (MCP1; officially known as C-C motif chemokine 2, CCL2) at K104, and this cleavage enhances its chemotactic potency significantly. Accumulating evidence reveals that MCP1 also disrupts the integrity of the blood-brain barrier (BBB). Here, we show that K104Stop-MCP1, truncated at the K104 where plasmin would normally cleave, is more efficient than the full-length protein (FL-MCP1) in compromising the integrity of the BBB in in vitro and in vivo models. K104Stop-MCP1 increases the permeability of BBB in both wild-type mice and mice deficient for tissue plasminogen activator (tPA), which converts plasminogen into active plasmin, suggesting that plasmin-mediated truncation of MCP1 plays an important role in BBB compromise. Furthermore, we show that the mechanisms underlying MCP1-induced BBB disruption involve redistribution of tight junction proteins (occludin and ZO-1) and reorganization of the actin cytoskeleton. Finally, we show that the redistribution of ZO-1 is mediated by phosphorylation of ezrin-radixin-moesin (ERM) proteins. These findings identify plasmin as a key signaling molecule in the regulation of BBB integrity and suggest that plasmin inhibitors might be used to modulate diseases accompanied by BBB compromise.

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Visualization of Chemokine Receptor Activation in Transgenic Mice Reveals Peripheral Activation of CCR2 Receptors in States of Neuropathic Pain

Cited by 123 publications

References 54 publications

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

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