Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms

Abstract

Background: Subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor prognosis once after the onset despite of the modern technical advancement. The development of a novel therapeutic modality to prevent rupture or a diagnostic method to stratify dangerous lesions from many stable ones is thus mandatory for social health. To this end, mechanisms underlying rupture of lesions should be clarified. Methods: We and others have developed the rat model in which induced IAs spontaneously rupture resulting in subarachnoid hemorrhage. To clarify molecular cascades regulating rupture, we obtained gene expression profile data from rupture-prone lesions and revealed the enrichment of neutrophil-related terms in rupture-prone lesions by Gene Ontology analysis. Next, to validate a role of neutrophils in rupture of lesions, G-CSF was administered to a rat model. Results: As a result, G-CSF treatment not only increased number of neutrophils infiltrating in lesions but also significantly facilitated rupture of the lesions without increase the incidence. To clarify mechanisms how neutrophils facilitate rupture of IAs, we used HL-60 cell line and found that inflammatory stimuli enhanced the collagenolytic activity of MMP9. Immunohistochemical study using IA lesions from a rat model identified neutrophils as a major type of cells producing MMP9 around a site of rupture and consistently the collagenolytic activity of MMP9 was detected in ruptured lesions. Conclusions: These results combined together suggest the crucial role of neutrophil to rupture of IAs and also propose the potential of this type of cells as a candidate of therapeutic or diagnostic targets.