Novel expression and localization of active thrombomodulin on the surface of mouse brain astrocytes

Pindon, Armelle; Hantaı̈, Daniel; Jandrot‐Perrus, Martine; Festoff, Barry W.

doi:10.1002/(sici)1098-1136(199703)19:3<259::aid-glia8>3.0.co;2-u

Cited by 29 publications

(20 citation statements)

References 64 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Third, other potential thrombin substrates or receptors that are absent in serum-free microglial cultures may compete with PARs for binding to thrombin in vivo. One such receptor is the membrane proteoglycan, thrombomodulin, that binds thrombin with a 100 -1000-fold greater affinity that we found active on brain astrocytes (34) and which may be neuroprotective for neurons (35). Consequently, there may be much fewer thrombin molecules available to actually bind and activate PAR4.…”

Section: Discussionmentioning

confidence: 83%

Persistent Protease-activated Receptor 4 Signaling Mediates Thrombin-induced Microglial Activation

Suo

Citron

et al. 2003

Journal of Biological Chemistry

Self Cite

113

View full text Add to dashboard Cite

We have previously reported that thrombin, the ultimate serine protease in the coagulation cascades, is a proinflammatory agent that causes proliferation and activation of brain microglial cells. However, participation of its principal receptor, the protease-activated receptor 1 (PAR1) appears to be limited to promoting microglial proliferation and not induction of inflammatory mediators. In the present study, we now report that thrombin action in promoting inflammatory mediators from brain microglia is mediated through another thrombin receptor, PAR4. Here we show that the PAR4 agonist peptide (PAR4AP, GYPGKF), but not the PAR1AP (TRAP, SFLLRN), induced tumor necrosis factor-␣ (TNF-␣) production not only in cultured murine microglial cells in vitro but also in rat cortex in vivo. Down-regulation of PAR4 expression in microglial cultures by a specific antisense, but not a sense, oligonucleotide reduced PAR4AP-induced TNF-␣. Mechanistic studies indicated that, in comparison with PAR1 signaling, prolonged increase of [Ca 2؉ ] i and phosphorylation of p44/42 mitogen-activated protein kinases, as well as NFB activation may be responsible for PAR4AP-induced TNF-␣ production in microglia. Taken together, these results demonstrate that PAR4 activation mediates the potentially detrimental effects of thrombin on microglia, implying that perspectives of exploiting PAR1 as a potential anti-inflammatory target should be shifted toward PAR4 as a much more specific therapeutic target in brain inflammatory conditions associated with neurotrauma and neurodegenerations.

show abstract

Section: Discussionmentioning

confidence: 83%

Persistent Protease-activated Receptor 4 Signaling Mediates Thrombin-induced Microglial Activation

Suo

Citron

et al. 2003

Journal of Biological Chemistry

Self Cite

113

View full text Add to dashboard Cite

show abstract

“…A nonserpin thrombomodulin (CD141) is expressed by microglia and-endothelium after injury. This molecule reduces thrombin induced neuronal death, underlining the potential of CD141 as a therapeutic agent [63, 64]. …”

Section: Serpins Are a Family Of “Selfdefence” Proteins Expressed mentioning

confidence: 99%

The Regulation of the CNS Innate Immune Response Is Vital for the Restoration of Tissue Homeostasis (Repair) after Acute Brain Injury: A Brief Review

Griffiths

Gasque

Neal

2010

International Journal of Inflammation

View full text Add to dashboard Cite

Neurons and glia respond to acute injury by participating in the CNS innate immune response. This involves the recognition and clearance of “not self ” pathogens and “altered self ” apoptotic cells. Phagocytic receptors (CD14, CD36, TLR–4) clear “not self” pathogens; neurons and glia express “death signals” to initiate apoptosis in T cells.The complement opsonins C1q, C3, and iC3b facilitate the clearance of apoptotic cells by interacting with CR3 and CR4 receptors. Apoptotic cells are also cleared by the scavenger receptors CD14, Prs-R, TREM expressed by glia. Serpins also expressed by glia counter the neurotoxic effects of thrombin and other systemic proteins that gain entry to the CNS following injury. Complement pathway and T cell activation are both regulated by complement regulatory proteins expressed by glia and neurons. CD200 and CD47 are NIRegs expressed by neurons as “don't eat me” signals and they inhibit microglial activity preventing host cell attack. Neural stem cells regulate T cell activation, increase the Treg population, and suppress proinflammatory cytokine expression. Stem cells also interact with the chemoattractants C3a, C5a, SDF-1, and thrombin to promote stem cell migration into damaged tissue to support tissue homeostasis.

show abstract

“…TM, an integral membrane chondroitin sulfate proteoglycan, complexes with thrombin and inhibits its activity (Esmon, 1987). TM appears to be active in the human and murine CNS (Pindon et al, 1997; Wong et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Inefficacy of F‐18 fluorodeoxy‐D‐glucose‐positron emission tomography scans for initial evaluation in early‐stage cutaneous melanoma

Wagner

Schauwecker

Davidson

et al. 2005

Cancer

143

View full text Add to dashboard Cite

Objective Selective focal MR‐Signal (diffusion‐) changes in the CA‐1 sector of the hippocampus have been described in transient global amnesia (TGA), but the pathophysiological substrate of these lesions is largely unknown. As several imaging and epidemiological findings point to a vascular origin an analysis of the temporal evolution of the hippocampal apparent diffusion coefficient (ADC) changes may offer new understanding of the pathomechanisms of TGA. Methods The time course of the ADC of hippocampal DWI lesions in TGA patients was studied using serial 3 T high‐resolution MR‐imaging within 1‐10 days as well as 4‐6 months after TGA. ADC values from 76 MR‐studies were analyzed and expressed as ratio ADC (rADC) in reference to the unaffected hemisphere. Results Twenty‐nine patients with TGA showed 34 DWI lesions with corresponding T2 lesions in the CA‐1 sector of the hippocampal cornu ammonis within a time window of 24‐72 h after onset. Ratio ADC decreased below 1.0 (0.66 ± 0.08) 24 h after the acute TGA episode and did show a further significant decrease to 0.57 ± 0.1 after 3 days (p < 0.05). After 72 h, rADC increased and normalized around day 10 with rADC values of 1.0 (p < 0.05). Interpretation The temporal evolution of the rADC in hippocampal signal changes in TGA shows a time course previously described for ischemic lesions in human stroke patients. This might imply a vascular origin of diffusion changes leading to a transient perturbation of memory relevant circuits in the hippocampus. Ann Neurol 2007

show abstract

Novel expression and localization of active thrombomodulin on the surface of mouse brain astrocytes

Cited by 29 publications

References 64 publications

Persistent Protease-activated Receptor 4 Signaling Mediates Thrombin-induced Microglial Activation

Persistent Protease-activated Receptor 4 Signaling Mediates Thrombin-induced Microglial Activation

The Regulation of the CNS Innate Immune Response Is Vital for the Restoration of Tissue Homeostasis (Repair) after Acute Brain Injury: A Brief Review

Inefficacy of F‐18 fluorodeoxy‐D‐glucose‐positron emission tomography scans for initial evaluation in early‐stage cutaneous melanoma

Contact Info

Product

Resources

About