Role of CCR2 in Inflammatory Conditions of the Central Nervous System

Chu, Hannah X; Arumugam, Thiruma V.; Gelderblom, Mathias; Magnus, Tim; Drummond, Grant Raymond; Sobey, Christopher G.

doi:10.1038/jcbfm.2014.120

Cited by 137 publications

(122 citation statements)

References 65 publications

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“…23 Consistent with this concept, a more detailed analysis of the monocyte subpopulations in blood revealed Ly6C hi monocytes to be selectively increased (whereas Ly6C lo monocytes were reduced) after stroke, and that INCB3344 prevented the increase in Ly6C hi cells ( …”

Section: Incb3344 Selectively Reduced Circulating and Infiltrating Lymentioning

confidence: 62%

Evidence That Ly6C ^hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization

Chu

Broughton

Kim

et al. 2015

Stroke

129

122

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Background and Purpose-Ly6Chi monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6C hi monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6C hi monocytes recruited into the brain early after ischemic stroke. Methods-Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. Results-Ly6Chi monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. Conclusions-Our data suggest that Ly6Chi monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization. Furthermore, there is evidence that CCR2/CCL2 mechanisms are important for the migration of neuroblasts from neurogenic regions to damaged regions of brain after cerebral ischemia in mice, suggesting a role in tissue recovery after stroke. 17 Thus, for the development of future therapies to target detrimental elements of the poststroke acute inflammatory response, it is vital to clarify the role of CCR2 + /Ly6C hi monocytes. To our knowledge, no study has examined the effect of a selective CCR2 antagonist in ischemic stroke. INCB3344 is a novel CCR2 antagonist that inhibits the binding of CCL2 to monocytes with high potency and it is highly selective for the CCR2 receptor.18 It effectively reduces monocyte/macrophage accumulation in autoimmune encephalomyelitis in mice and in inflammatory arthritis in rats 18 and in deoxycorticosterone acetate/salt-induced hypertension in mice.19 Its potency and selectivity for CCR2 inhibition have thus been used in this study to evaluate the effect of inhibiting Ly6C hi monocyte migration to the brain early during poststroke inflammation. Materials and Methods AnimalsThis study was approved by the Monash University Animal Ethics Committee (Project MARP/2011/112) and performed in accordance with the National Health and Medical Research Council of Australia guidelines for the care and use ...

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Section: Incb3344 Selectively Reduced Circulating and Infiltrating Lymentioning

confidence: 62%

Evidence That Ly6C ^hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization

Chu

Broughton

Kim

et al. 2015

Stroke

129

122

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“…CCR2 is mainly expressed on a subset of monocytes (inflammatory, CD45 hi Ly6C hi monocytes) and is important in monocyte mobilization out of the bone marrow and recruitment to tissues (including brain) in inflammatory states [54, 58]. Indeed, Ccr2 −/− mice have significantly reduced numbers of circulating inflammatory monocytes with a corresponding accumulation of these cells in the bone marrow, indicating their non-physiological retention [59] (Figure 3).…”

Section: Strategies Aimed At Chemokine Signalingmentioning

confidence: 99%

Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell–cell communication by chemokines

Gyoneva

Ransohoff

2015

Trends in Pharmacological Sciences

288

223

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Traumatic brain injury (TBI) affects millions of people worldwide every year. The primary impact initiates the secretion of pro- and anti-inflammatory factors, subsequent recruitment of peripheral immune cells and activation of brain-resident microglia and astrocytes. Chemokines are major mediators of peripheral blood cell recruitment to damaged tissue, including the TBI brain. Here we review the involvement of specific chemokine pathways in TBI pathology and attempts to modulate these pathways for therapeutic purposes. We focus on chemokine (C-C motif) ligand 2/chemokine (C-C motif) receptor 2 (CCL2/CCR2) and chemokine (C-X-C motif) ligand 12/chemokine (C-X-C motif) receptor 4 (CXCL12/CXCR4). Recent micro-array and multiplex expression profiling have also implicated CXCL10 and CCL5 in TBI pathology. Chemokine (C-X3-C motif) ligand 1/ chemokine (C-X3-C motif) receptor 1 (CX3CL1/CX3CR1) signaling in the context of TBI is also discussed. Current literature suggests that modulating chemokine signaling, especially CCL2/CCR2, may be beneficial in TBI treatment.

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“…In addition to CCR2, Ly6C is also expressed at high levels in monocytes recruited to inflamed tissues (11,36). The myeloid cell population was identified in brain 4 d after SE using CD11b (Fig.…”

Section: Se (mentioning

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.

288

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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Role of CCR2 in Inflammatory Conditions of the Central Nervous System

Cited by 137 publications

References 65 publications

Evidence That Ly6C ^hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization

Evidence That Ly6C ^hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization

Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell–cell communication by chemokines

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

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Role of CCR2 in Inflammatory Conditions of the Central Nervous System

Cited by 137 publications

References 65 publications

Evidence That Ly6C hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization

Evidence That Ly6C hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization

Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell–cell communication by chemokines

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

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Product

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Evidence That Ly6C ^hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization

Evidence That Ly6C ^hi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization