IL-27 receptor signaling regulated stress myelopoiesis drives Abdominal Aortic Aneurysm development

Abstract

Abdominal Aortic Aneurysm (AAA) is a vascular disease, where aortic wall degradation is mediated by accumulated immune cells. Though cytokines regulate the inflammatory milieu within the aortic wall, their contribution to AAA through distant alterations, particularly in the control of hematopoietic stem cells proliferation and myeloid cell differentiation remains poorly defined. Here we report an unexpected pathogenic role for interleukin-27 receptor (IL-27R) in AAA development as genetic inactivation of IL-27R protected mice from AAA induced by Angiotensin (Ang) II. The mitigation of AAA in IL-27R deficient mice is associated with a blunted accumulation of myeloid cells in suprarenal aortas due to the surprising attenuation of Ang II-induced expansion of HSCs. The loss of IL-27R engages transcriptional programs that promote HSCs quiescence and suppresses myeloid lineage differentiation, decreasing mature cell production and myeloid cell accumulation in the aorta. We, therefore, illuminate how a prominent vascular disease can be distantly driven by cytokine dependent regulation of the bone marrow precursors.