IL-27 Receptor Signaling potentiates Angiotensin II induced myelopoiesis and promotes Abdominal Aortic Aneurysm

Abstract

Abstract Abdominal Aortic Aneurysm (AAA) is a vascular disease, where aortic wall degradation is in part mediated by the accumulation of immune cells leading to aortic wall rupture and bleeding which is often fatal for the patient. Smoking, age, male gender, hypertension and atherosclerosis are major risk factors, however the mechanism of AAA development is still elusive. Though cytokines regulate the inflammatory milieu within the aortic wall, their possible role in systemic regulation of this disease, particularly in the control of hematopoietic stem cell proliferation, myeloid cell differentiation and their subsequent accumulation in AAA remains poorly defined. Here we report an unexpected pathogenic role of IL-27R signaling in the development of AAA. We found that in an animal model of AAA, prolonged infusion of Angiotensin (Ang) II robustly induces AAA formation in hyperlipidemic Apoe−/− and Apoe−/−Il27ra+/− mice but not in IL-27R deficient Apoe−/− mice. This mitigation of AAA formation in Apoe−/−Il27ra−/− mice is associated with a blunted accumulation of myeloid cells in suprarenal aortas due to a reduction of Ang II-induced hematopoietic stem and progenitor cell (HSPCs) expansion. We found that the absence of IL-27R signaling engages transcriptional programs that promote HSCs self-renewal program and suppress myeloid lineage differentiation, resulting in decreased mature myeloid cell production and thus a concomitant lack of Ang II-induced myeloid cell accumulation in the suprarenal aortas. Collectively, these data demonstrate that IL-27R signaling influences AAA development by potentiating Ang II induced myelopoiesis and may represent a molecular point of therapeutic intervention in AAA.