IL-27 receptor-regulated stress myelopoiesis drives abdominal aortic aneurysm development

Iuliia O. Peshkova, Turan Aghayev, Aliia R. Fatkhullina, Petr Makhov, Elizaveta K. Titerina, Satoru Eguchi, Yin Fei Tan, Andrew V. Kossenkov, Marina V. Khoreva, Lyudmila V. Gankovskaya, Stephen M. Sykes and Ekaterina K. Koltsova ()
Additional contact information
Iuliia O. Peshkova: Fox Chase Cancer Center
Turan Aghayev: Fox Chase Cancer Center
Aliia R. Fatkhullina: Fox Chase Cancer Center
Petr Makhov: Fox Chase Cancer Center
Elizaveta K. Titerina: Fox Chase Cancer Center
Satoru Eguchi: Temple University Cardiovascular Research Center
Yin Fei Tan: Fox Chase Cancer Center
Andrew V. Kossenkov: The Wistar Institute
Marina V. Khoreva: Pirogov Russian National Research Medical University
Lyudmila V. Gankovskaya: Pirogov Russian National Research Medical University
Stephen M. Sykes: Fox Chase Cancer Center
Ekaterina K. Koltsova: Fox Chase Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Abdominal aortic aneurysm (AAA) is a prevalent life-threatening disease, where aortic wall degradation is mediated by accumulated immune cells. Although cytokines regulate inflammation within the aorta, their contribution to AAA via distant alterations, particularly in the control of hematopoietic stem cell (HSC) differentiation, remains poorly defined. Here we report a pathogenic role for the interleukin-27 receptor (IL-27R) in AAA, as genetic ablation of IL-27R protects mice from the disease development. Mitigation of AAA is associated with a blunted accumulation of myeloid cells in the aorta due to the attenuation of Angiotensin II (Ang II)-induced HSC expansion. IL-27R signaling is required to induce transcriptional programming to overcome HSC quiescence and increase differentiation and output of mature myeloid cells in response to stress stimuli to promote their accumulation in the diseased aorta. Overall, our studies illuminate how a prominent vascular disease can be distantly driven by a cytokine-dependent regulation of bone marrow precursors.

Date: 2019
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DOI: 10.1038/s41467-019-13017-4

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