CCR2 Antagonism Alters Brain Macrophage Polarization and Ameliorates Cognitive Dysfunction Induced by Traumatic Brain Injury

Morganti, Josh M.; Jopson, Timothy; Liu, Sharon; Riparip, Lara‐Kirstie; Guandique, Cristian K.; Gupta, Nalin; Ferguson, Adam R.; Rosi, Susanna

doi:10.1523/jneurosci.2405-14.2015

Cited by 207 publications

(315 citation statements)

References 71 publications

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“…Blood-borne monocytes have been shown to infiltrate damaged or diseased brain tissue in animal models of other human neurological disease, such as the EAE model of multiple sclerosis (35), Alzheimer's disease (27,28,44), and traumatic brain injury (13,45). Previous studies have also reported elevated numbers of peripheral immune leukocytes after epileptiform activity (46,47).…”

Section: Discussionmentioning

confidence: 99%

“…We found several benefits on disease outcome by preventing entry of CCR2 + monocytes into the brain, including dampened inflammation, reduced number of Iba1 + myeloid cells, ameliorated neuronal damage, reduced opening of the BBB, and accelerated weight regain. CCR2 antagonists are efficacious after traumatic brain injury (45) and have entered clinical trials for neuropathic pain treatment (66). We propose that selective targeting of myeloid cell subsets via chemokine receptors will allow manipulation of specific immune cell types in the brain after injury or during disease.…”

Section: Discussionmentioning

confidence: 99%

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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.

275

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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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.

275

291

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“…32,33 Morganti and colleagues recently evaluated a CCR2 antagonist (CCX872) in CX3CR1GFP/+CCR2RFP/+ reporter mice using the 34 CCR2 antagonism also improved cognitive function recovery after TBI, as demonstrated by increased performance of CCX872-treated mice in a radial arm water maze test at 28 days post-injury. 34 They also showed that CCR2-positive infiltrating macrophages in the brain expressed both M1-and M2-like markers acutely after TBI, with sequential activation of M1-, followed by M2a-, and finally M2c-marker expression. 34 However, the accumulation of CCR2-positive macrophages into the TBI brain ultimately resulted in up-regulation of pro-inflammatory M1-like cells with neurotoxic potential, and CCR2 antagonism robustly reduced this pro-inflammatory profile and ameliorated the long-term cognitive dysfunction induced by TBI.…”

Section: Fig 7 (Continued)mentioning

confidence: 94%

“…34 However, the accumulation of CCR2-positive macrophages into the TBI brain ultimately resulted in up-regulation of pro-inflammatory M1-like cells with neurotoxic potential, and CCR2 antagonism robustly reduced this pro-inflammatory profile and ameliorated the long-term cognitive dysfunction induced by TBI. 34 These studies highlight a significant contribution of infiltrating macrophage to polarization after TBI, and further research is needed to understand mechanisms driving the trafficking of macrophages subsets to the TBI brain, how they interact with and modulate resident glial cells (microglia and astrocytes), and their role in chronic neurodegeneration following TBI.…”

Section: Fig 7 (Continued)mentioning

confidence: 99%

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Kumar

Álvarez‐Croda

Stoica

et al. 2016

Journal of Neurotrauma

270

271

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Activated microglia and macrophages exert dual beneficial and detrimental roles after central nervous system injury, which are thought to be due to their polarization along a continuum from a classical pro-inflammatory M1-like state to an alternative anti-inflammatory M2-like state. The goal of the present study was to analyze the temporal dynamics of microglia/macrophage polarization within the lesion micro-environment following traumatic brain injury (TBI) using a moderate-level controlled cortical impact (CCI) model in mice. We performed a detailed phenotypic analysis of M1-and M2-like polarized microglia/macrophages, as well as nicotinamide adenine dinucleotide phosphate oxidase (NOX2) expression, through 7 days post-injury using real-time polymerase chain reaction (qPCR), flow cytometry and image analyses. We demonstrated that microglia/macrophages express both M1-and M2-like phenotypic markers early after TBI, but the transient up-regulation of the M2-like phenotype was replaced by a predominant M1-or mixed transitional (Mtran) phenotype that expressed high levels of NOX2 at 7 days post-injury. The shift towards the M1-like and Mtran phenotype was associated with increased cortical and hippocampal neurodegeneration. In a follow up study, we administered a selective NOX2 inhibitor, gp91ds-tat, to CCI mice starting at 24 h post-injury to investigate the relationship between NOX2 and M1-like/Mtran phenotypes. Delayed gp91ds-tat treatment altered M1-/M2-like balance in favor of the anti-inflammatory M2-like phenotype, and significantly reduced oxidative damage in neurons at 7 days post-injury. Therefore, our data suggest that despite M1-like and M2-like polarized microglia/macrophages being activated after TBI, the early M2-like response becomes dysfunctional over time, resulting in development of pathological M1-like and Mtran phenotypes driven by increased NOX2 activity.

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“…We hypothesized that TBI-induced sustained eIF2α phosphorylation in the hippocampus, a brain region crucially involved in memory formation, could be a major contributor to the permanent cognitive dysfunction observed after TBI (34). To test this notion, we investigated whether treatment with ISRIB, several weeks postinjury, could remedy TBI-induced impairments in cognitive function and associated changes in synaptic function.…”

mentioning

confidence: 99%

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Chou

Krukowski

Jopson

et al. 2017

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

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Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampaldependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head traumainduced chronic cognitive deficits.brain trauma | memory deficits | translational control | eIF2α | hippocampus T raumatic brain injury (TBI) represents a major mental health problem (1-4). Even a mild TBI can elicit cognitive deficits, including permanent memory dysfunction (2, 4). Moreover, TBI is one of the most predictive environmental risk factors for the development of Alzheimer's disease and other forms of dementia (5-9). Current treatments have focused primarily on reducing the risk of TBI incidence, immediate neurosurgical intervention, or broad behavioral rehabilitation (10-13). Despite posing a huge societal problem, there are currently no pharmacological treatment options for patients that suffer from TBIinduced cognitive deficits.The integrated stress response (ISR) is an evolutionarily conserved pathway that controls cellular homeostasis and function (14). The central ISR regulatory step is the phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α) by a family of four eIF2α kinases (15, 16). Phosphorylation of eIF2α leads to inhibition of general protein synthesis, but also, to the translational up-regulation of a select subset of mRNAs (17, 18). In the brain, phosphorylation of eIF2α regulates the formation of long-term memory (19)(20)(21). Briefly, animals with reduced phosphorylation of eIF2α show enhanced long-term memory storage (19,(22)(23)(24), and increased phosphorylation of eIF2α in the brain prevents the formation of long-term memory (19,24,25).Similar to other chronic cognitive disorders (21, 26), TBI leads to a persistent activation of the ISR. TBI induces eIF2α phosphorylation even in brain regions that are distal to the injury site (27, 28). How...

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CCR2 Antagonism Alters Brain Macrophage Polarization and Ameliorates Cognitive Dysfunction Induced by Traumatic Brain Injury

Cited by 207 publications

References 71 publications

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

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

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

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