Abstract Body: Introduction: Clinical studies have shown an association between aging and the risk of intracranial aneurysm rupture. Aging leads to various changes in cellular homeostasis, including the onset of cellular senescence. Senescent cells secrete senescence-associated secretory phenotypes that leads to chronic vascular inflammation and abnormal vascular remodeling. Our preliminary data showed the accumulation of senescent cells in both human and mouse intracranial aneurysms, suggesting their potential role in the pathophysiology of intracranial aneurysms. We also confirmed that genetic elimination of senescent cells prevented aneurysm rupture. The immune system plays a critical role in eliminating senescent cells. However, in the pathological state, senescent cells can interfere with innate and adaptive immune responses through mechanisms known as immune checkpoints. Senescent cells express programmed cell death ligand 1 (PD-L1), which can bind to the programmed cell death protein 1 (PD-1) on immune cells. PD-L1-expressing senescent cells then evade clearance by immune cells. We investigated the effect of an immune checkpoint inhibitor on the development of intracranial aneurysm rupture.
Methods: We used 15-month-old male C57BL/6J mice (n = 29). We induced intracranial aneurysms by a combination of elastase injection and hypertension. After aneurysm induction, we started treatment with anti-PD-1 antibody as an immune checkpoint inhibitor or IgG2 as a vehicle. We compared the aneurysm formation and rupture rates, and the survival curve between the two groups. We also assessed the effects of anti-PD-1 antibody on the mRNA expression of p16 as a senescent cell marker in cerebral arteries.
Results: The aneurysm rupture rate was significantly lower in the treatment group than in the vehicle group (54.5% vs. 100%, P<0.05, Fig. A and B). There was no statistical difference in the aneurysm formation rate between the two groups (78.6% vs. 71.4%, P>0.99, Fig. A). Mice treated with anti-PD-1 antibody had a better survival rate than the control group (P=0.053, Fig. C). Treatment with anti-PD-1 antibody significantly reduced the mRNA expression of p16 in cerebral arteries (P<0.05, Fig. D).
Conclusions: Treatment with immune checkpoint inhibitor prevented intracranial aneurysm rupture. Our findings suggest that cellular senescence and immune checkpoint may serve as novel therapeutic targets for the prevention of aneurysm rupture.