Regulation of chemokines and chemokine receptors after experimental closed head injury

Otto, Vivianne I.; Stahel, Philip F.; Rancan, Mario; Kariya, Karin; Shohami, Esther; Yatsiv, Ido; Eugster, Hans-Pietro; Kossmann, Thomas; Trentz, O; Morganti-Kossmann, Maria Cristina

doi:10.1097/00001756-200107030-00053

Cited by 49 publications

(32 citation statements)

References 22 publications

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“…A prominent chemokine receptor implicated in resident microglial migration in the literature is CCR5. It has been shown to be constitutively expressed in resting microglia (Simpson et al, 2000;Otto et al, 2001) and upregulated in diverse pathological states (Mennicken et al, 2002;Glabinski et al, 2003;Natale et al, 2003). Additionally, many CCR5 ligands such as MIP-1␣/CCL3, MIP-1␤/CCL4, and RANTES/CCL5 are released after neural injury (Ghirnikar et al, 1996;Babcock et al, 2003;Marella and Chabry, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Other possible chemokine receptor candidates include CCR1, CCR3, CX3CR1, and CXCR3 (Maciejewski-Lenoir et al, 1999;Bajetto et al, 2002;Flynn et al, 2003); however, relative contributions likely depend on injury stimulus. The intrinsic chemokines for CCR5 have been studied previously after stab lesion (Ghirnikar et al, 1996) and in other injury models (Baker et al, 1999;Otto et al, 2001;Babcock et al, 2003;Marella and Chabry, 2004). A candidate common to all models is RANTES/CCL5.…”

Section: Discussionmentioning

confidence: 99%

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Migration of Perilesional Microglia after Focal Brain Injury and Modulation by CC Chemokine Receptor 5: AnIn SituTime-Lapse Confocal Imaging Study

Carbonell

Murase²,

Horwitz³

et al. 2005

J. Neurosci.

121

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Microglia rapidly become reactive in response to diverse stimuli and are thought to be prominent participants in the pathophysiology of both acute injury and chronic neurological diseases. However, mature microglial reactions to a focal lesion have not been characterized dynamically in adult vertebrate tissue. Here, we present a detailed analysis of long-distance perilesional microglial migration using time-lapse confocal microscopy in acutely isolated living slices from adult brain-injured mice. Extensive migration of perilesional microglia was apparent by 24 h after injury and peaked at 3 d. Average instantaneous migration speeds of ϳ5 m/min and peak speeds Ͼ10 m/min were observed. Collective, directed migration toward the lesion edge was not observed as might be expected in the presence of chemoattractive gradients. Rather, migration was autonomous and could be modeled as a random walk. Pharmacological blockade of the cysteine-cysteine chemokine receptor 5 reduced migration velocity and the number of perilesional migratory microglia without affecting directional persistence, suggesting a novel role for chemokines in modulation of discrete migratory parameters. Finally, activated microglia in the denervated hippocampal stratum oriens did not migrate extensively, whereas human immunodeficiency virus-1 tat-activated microglia migrated nearly twice as fast as those at the stab lesion, indicating a nonuniform microglial response to different stimuli. Understanding the characteristics and specific molecular mechanisms underlying microglial migration after neural injury could reveal novel targets for therapeutic strategies for modulating neuroinflammation in human diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Migration of Perilesional Microglia after Focal Brain Injury and Modulation by CC Chemokine Receptor 5: AnIn SituTime-Lapse Confocal Imaging Study

Carbonell

Murase²,

Horwitz³

et al. 2005

J. Neurosci.

121

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“…Using the ependymal route, described by Martino et al (26), allows vectors to distribute throughout cerebrospinal fluid (CSF) and infect ependymal and leptomeningeal cells, which in turn secrete the product of the transgene into the CSF. This route avoids the traumatic effects of tissue injury associated with intraparenchymal and intracerebroventricular injections, which can include chemokine production and disruption of the blood-brain barrier (27)(28)(29)(30).…”

Section: Ifn-␥-induced Chemokines Synergize With Pertussis Toxin To Pmentioning

confidence: 99%

“…However, AdIFN␥ did not induce expression beyond baseline levels of other chemokines, including CXCL2, CCL2/ MCP-1, or CCL3/MIP-1␣ (data not shown). These chemokines have been implicated in CNS inflammatory responses (25,30,39,40), and their absence in this system suggests that other signals in addition to IFN-␥ are required for immune pathology.…”

Section: Intrathecal Ifn-␥ Induces Selective Chemokine Expression In Cnsmentioning

confidence: 99%

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

Millward

Caruso

Campbell

et al. 2007

The Journal of Immunology

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Inflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-γ, a cytokine not normally expressed in the CNS. To investigate the role of IFN-γ in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-γ (AdIFNγ) to IFN-γ-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-γ that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-γ induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-γR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-γ-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-γ vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-γ induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-γ-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.

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“…These findings confirm the historic notion that lymphocytes do not represent important effector cells of the immunological response to TBI, in contrast to neutrophils and monocytes/macrophages, and activated microglia (Bellander et al, 2010;Biagas et al, 1992;Ramlackhansingh et al, 2011;Rhodes, 2011;SzmydyngerChodobska et al, 2011). In fact, we have shown that neutrophils infiltrate the injured brain within 24 h in the present model of closed head injury in mice, and that cellular infiltration is largely regulated by chemokines and chemokine receptors expressed by neutrophils, macrophages, and resident cells of the CNS (Otto et al, 2001;Stahel et al, 2000). The only relevant differences in outcome parameters analyzed in this study consisted of significantly attenuated serum levels of the complement activation fragment C3a (Fig.…”

Section: Closed Head Injury In Immunodeficient Rag1mentioning

confidence: 56%

Challenging the Role of Adaptive Immunity in Neurotrauma: Rag1^−/− Mice Lacking Mature B and T Cells Do Not Show Neuroprotection after Closed Head Injury

Weckbach

Neher

Losacco

et al. 2012

Journal of Neurotrauma

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The role of adaptive immunity in contributing to post-traumatic neuroinflammation and neuropathology after head injury remains largely unexplored. The present study was designed to investigate the pathophysiological sequelae of closed head injury in Rag1 -/ -mice devoid of mature B and T lymphocytes. C57BL/6 wild-type and Rag1 -/ -mice were subjected to experimental closed head injury, using a standardized weight-drop device. Outcome parameters consisted of neurological scoring, quantification of blood-brain barrier (BBB) function, measurement of inflammatory markers and mediators of apoptosis in serum and brain tissue, and assessment of neuronal cell death, astrogliosis, and tissue destruction. There was no difference between wild-type and Rag1-/ -mice with regard to injury severity and neurological impairment for up to 7 days after head injury. The extent of BBB dysfunction was in a similar range for both groups. Quantification of complement activation fragments in serum revealed significantly attenuated C3a levels in Rag1 -/ -mice compared to wild-type animals. In contrast, the levels of pro-and anti-inflammatory cytokines and pro-apoptotic and anti-apoptotic mediators remained in a similar range for both groups, and the histological analysis of brain sections did not reveal a difference in reactive astrogliosis, tissue destruction, and neuronal cell death in Rag1 -/ -compared to wild-type mice. These findings suggest that adaptive immunity is not of crucial importance for initiating and sustaining the inflammatory neuropathology after closed head injury. The attenuated extent of post-traumatic complement activation seen in Rag1 -/ -mice implies a cross-talk between innate and adaptive immune responses, which requires further investigation in future studies.

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Regulation of chemokines and chemokine receptors after experimental closed head injury

Cited by 49 publications

References 22 publications

Migration of Perilesional Microglia after Focal Brain Injury and Modulation by CC Chemokine Receptor 5: AnIn SituTime-Lapse Confocal Imaging Study

Migration of Perilesional Microglia after Focal Brain Injury and Modulation by CC Chemokine Receptor 5: AnIn SituTime-Lapse Confocal Imaging Study

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

Challenging the Role of Adaptive Immunity in Neurotrauma: Rag1^−/− Mice Lacking Mature B and T Cells Do Not Show Neuroprotection after Closed Head Injury

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Regulation of chemokines and chemokine receptors after experimental closed head injury

Cited by 49 publications

References 22 publications

Migration of Perilesional Microglia after Focal Brain Injury and Modulation by CC Chemokine Receptor 5: AnIn SituTime-Lapse Confocal Imaging Study

Migration of Perilesional Microglia after Focal Brain Injury and Modulation by CC Chemokine Receptor 5: AnIn SituTime-Lapse Confocal Imaging Study

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

Challenging the Role of Adaptive Immunity in Neurotrauma: Rag1−/− Mice Lacking Mature B and T Cells Do Not Show Neuroprotection after Closed Head Injury

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Challenging the Role of Adaptive Immunity in Neurotrauma: Rag1^−/− Mice Lacking Mature B and T Cells Do Not Show Neuroprotection after Closed Head Injury