Early infiltration of CD8+ macrophages/microglia to lesions of rat traumatic brain injury

Zhang, Zhiren; Artelt, Matthias; Burnet, Michael; Trautmann, Katrin; Schluesener, Hermann J.

doi:10.1016/j.neuroscience.2006.04.027

Cited by 56 publications

(38 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, targeting the P2X4R-p38 -MAPKsignaling pathway in spinal microglia could prove useful in the development of novel therapeutic approaches for treating pain hypersensitivity caused by nerve injury. In addition, involvement of microglial P2X4Rs reported after injury to a peripheral nerve is increasingly being found in other models of CNS pathology such as inflammation Zhang et al, 2008), CNS injury (Schwab et al, 2005;Zhang et al, 2006), and in glioblastoma brain tumors (Guo et al, 2004). Therefore, the implications of our findings may extend not only to pathological pain states but also to a diversity of CNS disorders.…”

Section: Discussionmentioning

confidence: 57%

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

Trang¹,

Beggs²,

Wan³

et al. 2009

J. Neurosci.

422

378

View full text Add to dashboard Cite

Microglia in the dorsal horn of the spinal cord are increasingly recognized as being crucial in the pathogenesis of pain hypersensitivity after injury to a peripheral nerve. It is known that P2X4 purinoceptors (P2X4Rs) cause the release of brain-derived neurotrophic factor (BDNF) from microglia, which is necessary for maintaining pain hypersensitivity after nerve injury. However, there is a critical gap in understanding how activation of microglial P2X4Rs leads to the release of BDNF. Here, we show that stimulating P2X4Rs with ATP evokes a biphasic release of BDNF from microglia: an early phase occurs within 5 min, whereas a late phase peaks 60 min after ATP stimulation. Concomitant with the late phase of release is an increased level of BDNF within the microglia. Both phases of BDNF release and the accumulation within the microglia are dependent on extracellular Ca 2ϩ . The late phase of BDNF release and accumulation, but not the early phase of release, are suppressed by inhibiting transcription and translation, indicating that activation of P2X4R causes an initial release of a pre-existing pool of BDNF followed by an increase in de novo synthesis of BDNF. The release of BDNF is abolished by inhibiting SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated exocytosis. Furthermore, we find that the P2X4R-evoked release and synthesis of BDNF are dependent on activation of p38-mitogen-activated protein kinase (MAPK). Together, our findings provide a unifying mechanism for pain hypersensitivity after peripheral nerve injury through P2X4R-evoked increase in Ca 2ϩ and activation of p38-MAPK leading to the synthesis and exocytotic release of BDNF from microglia.

show abstract

Section: Discussionmentioning

confidence: 57%

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

Trang¹,

Beggs²,

Wan³

et al. 2009

J. Neurosci.

422

378

View full text Add to dashboard Cite

show abstract

“…59,63 We and others have shown that macrophages are a major component of the inflammatory immune response to TBI. 29,48,64,65 The macrophage inflammatory response can be beneficial to sterilize wounds, to clear necrotic debris and to promote wound repair. 66 In some models of CNS injury, such as spinal cord injury, there is evidence that macrophages suppress inflammation and are critical for recovery.…”

Section: Ccr2 In Traumatic Brain Injurymentioning

confidence: 99%

CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury

Hsieh

Niemi

Wang

et al. 2014

Journal of Neurotrauma

148

138

View full text Add to dashboard Cite

Traumatic brain injury (TBI) provokes inflammatory responses, including a dramatic rise in brain macrophages in the area of injury. The pathway(s) responsible for macrophage infiltration of the traumatically injured brain and the effects of macrophages on functional outcomes are not well understood. C-C-chemokine receptor 2 (CCR2) is known for directing monocytes to inflamed tissues. To assess the role of macrophages and CCR2 in TBI, we determined outcomes in CCR2-deficient (Ccr2 -/ -) mice in a controlled cortical impact model. We quantified brain myeloid cell numbers post-TBI by flow cytometry and found that Ccr2 -/ -mice had greatly reduced macrophage numbers (*80-90% reduction) early post-TBI, compared with wild-type mice. Motor, locomotor, and cognitive outcomes were assessed. Lack of Ccr2 improved locomotor activity with less hyperactivity in open field testing, but did not affect anxiety levels or motor coordination on the rotarod three weeks after TBI. Importantly, Ccr2-/ -mice demonstrated greater spatial learning and memory, compared with wildtype mice eight weeks after TBI. Although there was no difference in the volume of tissue loss, Ccr2 -/ -mice had significantly increased neuronal density in the CA1-CA3 regions of the hippocampus after TBI, compared with wild-type mice. These data demonstrate that Ccr2 directs the majority of macrophage homing to the brain early after TBI and indicates that Ccr2 may facilitate harmful responses. Lack of Ccr2 improves functional recovery and neuronal survival. These results suggest that therapeutic blockade of CCR2-dependent responses may improve outcomes following TBI.

show abstract

“…Macrophages with ED1 can be observed in the majority of brain tumors, as well as in gliomas (18). Cluster of differentiation 8 (CD8) was traditionally recognized as a marker that is mainly expressed in cytotoxic T cells and natural killer cells (19 (21). Thus, in the present study, multiple antigens were used to study the distribution and characteristics of tumor-associated macrophages/microglia in rat C6 glioma.…”

Section: Introductionmentioning

confidence: 96%

Distribution and characterization of tumor-associated macrophages/microglia in rat C6 glioma

2015

View full text Add to dashboard Cite

Abstract. Immunity responses and immunotherapy are novel areas of research for the pathological development and treatment of glioma, the most common brain cancer. Characterization of the subpopulations of infiltrated immune cells may aid in our understanding of the tumor immune response and contribute to the identification of cellular targets for selective immunotherapy. Using a rat C6 glioma model, the present study observed a significant heterogeneity of active macrophages and microglia, including cluster of differentiation 8 (CD8) + , endothelial monocyte-activating polypeptide II (EMAPII) + and ED1 + cells, mostly in the areas of compact tumor growth and inside or around the pannecrosis. Moreover, the CD8 + cells were similar to reactive ED1 + and EMAPII + microglia/macrophages in morphology and distribution, but different from the W3/13 + T cells. These observations suggest that different subtypes of macrophages and microglia are involved in glioma development and thus, may be potential targets for immunotherapeutic antitumor strategies. IntroductionGlioma, which occurs in the central nervous system (CNS), is the most common primary malignant tumor, with an unacceptably poor prognosis despite the application of a variety of treatments, including surgery, radiotherapy and chemotherapy (1). In recent years, accumulated data have established that the immune network may be involved in regulating glioma development and growth (2). Moreover, tumor cells have been killed following direct immunization experiments using vaccines in mice, indicating its role in specific protective immunity and tumor destruction mediated by immune cells, such as microglia/macrophages (3). These immunotherapies exert a highly specific, long-term fatal effect on tumor cells by stimulating and supplementing the body's antitumor immunity (4,5), with only minimal adverse reactions (6). However, in the past decade, the main debate has focused on whether immunity exhibits an antitumor role in the CNS or functions as a tumor growth promoter (7). Additionally, the functions and mechanism of different immune cells in glioma require further investigation.Various pathological stimuli, including brain injury (8), neurodegeneration (9), infection, inflammation (10) and brain tumors (11), can activate brain macrophages/microglia. It has been observed that in CNS tumors, activated microglia/macrophages can engulf tissue debris and secrete growth-promoting factors, leading to regeneration (12). By contrast, the overactivation of microglia/macrophages will lead to tissue damage in the CNS (13). Following activation, microglia/macrophages change their morphology, upregulate the expression of certain membrane proteins and produce certain cytokines, resulting in inflammation and tissue loss (14). The contrast in roles played by activated microglia/macrophages may be due to the existence of different subpopulations of microglia/macrophages (15).Endothelial monocyte-activating polypeptide II (EMAPII) + macrophages secrete proinflammatory and antiangiogenic ...

show abstract

Early infiltration of CD8+ macrophages/microglia to lesions of rat traumatic brain injury

Cited by 56 publications

References 44 publications

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury

Distribution and characterization of tumor-associated macrophages/microglia in rat C6 glioma

Contact Info

Product

Resources

About