Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells

Abstract

BackgroundIntracranial aneurysms (IA) are increasingly recognized as a disease driven by chronic inflammation. Recent research has identified key mediators and processes underlying IA pathogenesis, but mechanistic understanding remains incomplete. Lymphocytic infiltrates have been demonstrated in patient IA tissue specimens and have also been shown to play an important role in abdominal aortic aneurysms (AAA) and related diseases such as atherosclerosis. However, no study has systematically examined the contribution of lymphocytes in a model of IA.MethodsLymphocyte-deficient (Rag1) and wild-type (WT; C57BL/6 strain) mice were subjected to a robust IA induction protocol. Rates of IA formation and rupture were measured, and cerebral artery tissue was collected and utilized for histology and gene expression analysis.ResultsAt 2 weeks, the Rag1 group had significantly fewer IA formations and ruptures than the WT group. Histological analysis of unruptured IA tissue showed robust B and T lymphocyte infiltration in the WT group, while there were no differences in macrophage infiltration, IA diameter, and wall thickness. Significant differences in interleukin-6 (IL-6), matrix metalloproteinases 2 (MMP2) and 9 (MMP9), and smooth muscle myosin heavy chain (MHC) were observed between the groups.ConclusionsLymphocytes are key contributors to IA pathogenesis and provide a novel target for the prevention of IA progression and rupture in patients.

Soluble galectin 9 potently enhanced regulatory T‐cell formation, a pathway impaired in patients with intracranial aneurysm

“…Aneurysm‐infiltrating neutrophils and macrophages mediate the release of proteinases that degrade the extracellular matrix and the elastic lamina . Proinflammatory cytokines, including interleukin (IL)‐1, IL‐6, tumour necrosis factor (TNF)‐α and monocyte chemoattractant protein‐1 (MCP‐1), are released by infiltrating neutrophils, macrophages and lymphocytes and induce inflammation, proliferation and apoptosis in the endothelium and the smooth muscle cells, causing further tissue destruction and pathogenic remodaling . In contrast, reversal of the proinflammatory local environment and suppression of immune responses may help manage IA.…”

A functional polymorphism in the promoter region of miR‐155 predicts the risk of intracranial hemorrhage caused by rupture intracranial aneurysm

“…[31][32][33][34][35] Nevertheless, the effect of MMP-2 on the pathogenesis of IA is less defined, whereas a mouse model of MMP-2 knockout exhibited no difference in the prevalence of IA compared to that in WT mice. 36,37 However, an elevated MMP-2 and MMP-9 expression was observed in the tissue specimens of IA patients. 38,39 Moreover, Jin et al 40 have demonstrated a higher expression of MMPs 9 and 2 in ruptured IA.…”

“…Therefore, as a key regulator of ECM, MMPs are considered to play an essential role in the development of multiple disorders in the central nervous system as well as during the onset of IA . Nevertheless, the effect of MMP‐2 on the pathogenesis of IA is less defined, whereas a mouse model of MMP‐2 knockout exhibited no difference in the prevalence of IA compared to that in WT mice . However, an elevated MMP‐2 and MMP‐9 expression was observed in the tissue specimens of IA patients .…”

Intracranial aneurysm’s association with genetic variants, transcription abnormality, and methylation changes in ADAMTS genes

“…Additional experiments are needed for further verification. ADAMTSL1's binding to the extracellular matrix (Hirohata et al, 2002) may influence the degradation of extracellular matrix levels, which may contribute to IA development (Sawyer et al, 2016). Lower levels of ADAMTSL1 mRNA and protein in IA tissue may be associated with differential methylation (Yong, Hsu & Chen, 2016).…”

“…ADAMTSL1 is distinct from other genes in the ADAMTS family, and binds to the extracellular matrix in a spatially-specific manner (Hirohata et al, 2002). Because IA development is caused by changes such as the degeneration of the extracellular matrix (Sawyer et al, 2016), it is possible that ADAMTS protein dysfunction may contribute to the development of IA, but the exact mechanisms are unclear.…”