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Published on: July 25, 2011
ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice
M M Khan1, D G Motto, S R Lentz
1Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Background:
ADAMTS13 cleaves hyperactive ultra-large von Willebrand factor (ULVWF) multimers into smaller and less active forms. It remains unknown whether VWF-mediated inflammatory processes play a role in the enhanced brain injury due to ADAMTS13 deficiency.
Objective:
We tested the hypothesis that the deleterious effect of ADAMTS13 deficiency on ischemic brain injury is mediated through VWF-dependent enhanced vascular inflammation.
Methods:
Transient focal cerebral ischemia was induced by 60 min of occlusion of the right middle cerebral artery. Myeloperoxidase (MPO) activity and inflammatory cytokines in the infarcted region were evaluated 23 h after reperfusion injury. Neutrophil infiltration within the infarct and surrounding areas was quantitated by immunohistochemistry.
Results:
We report that ADAMTS13-deficient mice exhibited significantly enlarged infarct size, concordant with increased myeloperoxidase (MPO) activity, neutrophil infiltration and expression of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In contrast, VWF-deficient mice exhibited significantly reduced MPO activity, neutrophil infiltration and inflammatory cytokine induction, demonstrating a role of VWF in these inflammatory processes. Mice deficient for both ADAMTS13 and VWF exhibited an identical reduction of the same inflammatory parameters, demonstrating that the increased inflammation observed in ADAMTS13-deficient mice is VWF dependent. Finally, the increased infarct size observed in ADAMTS13-deficient mice was completely abrogated by prior immunodepletion of neutrophils, demonstrating a causal role for acute inflammation in the enhanced brain injury that occurs in the setting of ADAMTS13 deficiency.
Conclusion:
These findings provide new evidence for ADAMTS13 in reducing VWF-mediated acute cerebral inflammation following ischemic stroke.
Insights
ADAMTS13 deficiency exacerbates ischemic stroke injury by increasing VWF-mediated inflammation and neutrophil infiltration. Restoring ADAMTS13 function reduces brain damage, highlighting its protective role in stroke.
Area of Science:
- Neuroscience
- Hematology
- Immunology
Background:
- ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13) cleaves ultra-large von Willebrand factor (ULVWF) multimers.
- The role of VWF-mediated inflammation in ADAMTS13 deficiency-associated brain injury is unclear.
Purpose of the Study:
- To investigate if ADAMTS13 deficiency worsens ischemic brain injury via VWF-dependent vascular inflammation.
- To test the hypothesis that VWF-mediated inflammation contributes to stroke severity in ADAMTS13-deficient mice.
Main Methods:
- Transient focal cerebral ischemia induced by middle cerebral artery occlusion in mice.
- Evaluation of myeloperoxidase (MPO) activity, inflammatory cytokines (IL-6, TNF-α), and neutrophil infiltration in the infarct zone.
- Comparison between wild-type, ADAMTS13-deficient, VWF-deficient, and double-deficient mice, with and without neutrophil depletion.
Main Results:
- ADAMTS13-deficient mice showed larger infarcts, increased MPO activity, neutrophil infiltration, and elevated IL-6 and TNF-α.
- VWF deficiency reduced these inflammatory markers, indicating VWF's role in inflammation.
- Mice lacking both ADAMTS13 and VWF had reduced inflammation, confirming VWF dependence.
- Neutrophil depletion abrogated the increased infarct size in ADAMTS13-deficient mice.
Conclusions:
- ADAMTS13 deficiency exacerbates ischemic stroke injury through VWF-dependent inflammation.
- Neutrophils play a critical role in the enhanced brain injury observed in ADAMTS13 deficiency.
- ADAMTS13 protects against VWF-mediated cerebral inflammation post-ischemic stroke.
