ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice.
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.


CONCLUSIONS
These findings provide new evidence for ADAMTS13 in reducing VWF-mediated acute cerebral inflammation following ischemic stroke.
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
M M
MM
Khan
D G
DG
Motto
S R
SR
Lentz
A K
AK
Chauhan
D000071120:ADAMTS13 Protein; D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020293:Vasculitis, Central Nervous System / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D009195:Peroxidase; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein