Subarachnoid hemorrhage (SAH) is mainly attributable to the rupture of intracranial aneurysms (IAs). Although the outcome of SAH is considerably poor in spite of the recent intensive medical care, mechanisms regulating the progression of IAs or triggering rupture remain to be clarified, making the development of effective preemptive medicine to prevent SAH difficult. However, a series of recent studies have been expanding our understanding of the pathogenesis of IAs. These studies have suggested the crucial role of macrophage-mediated chronic inflammation in the pathogenesis of IAs. In histopathological analyses of IA lesions in humans and induced in animal models, the number of macrophages infiltrating in lesions is positively correlated with enlargement or rupture of IAs. In animal models, a genetic deletion or an inhibition of monocyte chemotactic protein-1, a major chemoattractant for macrophages, or a pharmacological depletion of macrophages consistently suppresses the development and progression of IAs. Furthermore, a macrophage-specific deletion of Ptger2 (gene for prostaglandin E receptor subtype 2) or a macrophage-specific expression of a mutated form of IκB α which inhibits nuclear translocation of nuclear factor κB significantly suppress the development of IAs, supporting the role of macrophages and the inflammatory signaling functioning there in the pathogenesis of IAs. The development of drug therapies suppressing macrophage-mediated inflammatory responses in situ can thus be a potential strategy in the pre-emptive medicine targeting SAH. In this manuscript, we summarize the experimental evidences about the pathogenesis of IAs focused on inflammatory responses and propose the definition of IAs as a macrophage-mediated inflammatory disease.

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Subarachnoid hemorrhage due to rupture of an intracranial aneurysm has a quite poor prognosis after the onset of symptoms, despite the modern technical advances. Thus, the mechanisms underlying the rupture of lesions should be clarified. To this end, we obtained gene expression profile data and identified the neutrophil-related enriched terms in rupture-prone lesions using Gene Ontology analysis. Next, to validate the role of neutrophils in the rupture of lesions, granulocyte-colony stimulating factor (G-CSF) was administered to a rat model, in which more than half of induced lesions spontaneously ruptured, leading to subarachnoid hemorrhage. As a result, G-CSF treatment not only increased the number of infiltrating neutrophils, but also significantly facilitated the rupture of lesions. To clarify the mechanisms of how neutrophils facilitate this rupture, we used HL-60 cell line and found an enhanced collagenolytic activity, corresponding to matrix metalloproteinase 9 (MMP9), upon inflammatory stimuli. The immunohistochemical analyses revealed the accumulation of neutrophils around the site of rupture and the production of MMP9 from these cells in situ. Consistently, the collagenolytic activity of MMP9 could be detected in the lysate of ruptured lesions. These results suggest the crucial role of neutrophils to the rupture of intracranial aneurysms; implying neutrophils as a therapeutic or diagnostic target candidate.