Journal Article

Interleukin-6 Promotes Murine Estrogen Deficiency-Associated Cerebral Aneurysm Rupture

Hosaka, Koji, Motwani, Kartik, Jones, Chad, Dodd, William, Wajima, Daisuke, Patel, Devan, Fazal, Hanain Z, Hoh, Brian L, Hourani, Siham

2020

Overview

Abstract BACKGROUND Estrogen deficiency is associated with cerebral aneurysm rupture, but the precise mechanism is unknown. OBJECTIVE To test the hypothesis that IL-6 is required for the increase in aneurysm rupture rate observed in estrogen-deficient mice. METHODS We analyzed IL-6 expression in human cerebral aneurysms. We induced cerebral aneurysms in estrogen-deficient female C57BL/6 mice that had undergone 4-vinylcyclohexene diepoxide (VCD) treatment or bilateral ovariectomy (OVE). Mice were blindly randomized to selective IL-6 inhibition (IL-6 receptor [IL-6R] neutralizing antibody, n = 25) or control (isotype-matched IgG, n = 28). Murine cerebral arteries at the circle of Willis were assessed for aneurysm rupture and macrophage infiltration. RESULTS IL-6 is expressed in human cerebral aneurysms, but not in control arteries. Serum IL-6 is elevated in ovariectomized female mice compared to sham control (14.3 ± 1.7 pg/mL vs 7.4 ± 1.5 pg/mL, P = .008). Selective IL-6R inhibition suppressed cerebral aneurysm rupture in estrogen-deficient mice compared with control (VCD: 31.6% vs 70.0%, P = .026; OVE: 28.6% vs 65.2%, P = .019). IL-6R inhibition had no effect on formation or rupture rate in wild-type mice. IL-6R neutralizing antibody significantly reduced macrophage infiltration at the circle of Willis (1.9 ± 0.2 vs 5.7 ± 0.6 cells/2500 μm2; n = 8 vs n = 15; P < .001). CONCLUSION IL-6 is increased in the serum of estrogen-deficient mice and appears to play a role in promoting murine estrogen deficiency-associated cerebral aneurysm rupture via enhanced macrophage infiltration at the circle of Willis. Inhibition of IL-6 signaling via IL-6 receptor neutralizing antibody inhibits aneurysm rupture in estrogen-deficient mice. IL-6 receptor inhibition had no effect on aneurysm formation or rupture in wild-type animals.

• Publisher: Oxford University Press,Copyright by the Congress of Neurological Surgeons,Wolters Kluwer Health, Inc
• Subject: Aneurysm, Ruptured - metabolism / Aneurysms / Animals / Complications and side effects / Deficiency diseases / Development and progression / Disease Models, Animal / Estrogen / Estrogens - deficiency / Female / Health aspects / Humans / Interleukin-6 / Interleukin-6 - metabolism / Intracranial Aneurysm - metabolism / Intracranial Aneurysm - pathology / Intracranial aneurysms / Mice / Mice, Inbred C57BL / Neurosurgery / Ovariectomy / Research—Laboratory / Rodents