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IL-27 Receptor Signaling Plays Key Role in Development of Abdominal Aortic Aneurysm

November 25, 2019

Dr. Koltsova's lab continues to study the role of certain inflammatory mitigators of interest in both cardiovascular disease and cancer to gain a better understanding of how they work and whether their functions are applicable for treatment or cause a harmful effect. Dr. Koltsova's lab continues to study the role of certain inflammatory mitigators of interest in both cardiovascular disease and cancer to gain a better understanding of how they work and whether their functions are applicable for treatment or cause a harmful effect.

PHILADELPHIA (November 25, 2019) – Researchers from Fox Chase Cancer Center have discovered that the IL-27 receptor, which is expressed on many of the body’s immune cells, plays an important role in the development of abdominal aortic aneurysm (AAA).

AAA is a cardiovascular disease characterized by destruction of the abdominal aortic wall. A break in the wall leads to blood spilling into the abdominal cavity, which can be fatal. Previous research had suggested that inflammation plays a role in the development of AAA, but the underlying inflammatory mechanisms were understudied.

Since AAA in humans is largely driven by elevated blood pressure, rather than by direct destruction of the aortic wall, Ekaterina Koltsova, MD, PhD, an associate professor in the Blood Cell Development and Function program at Fox Chase, and colleagues conducted a study in mice using an angiotensin II mouse model of AAA induction. Angiotensin II raises blood pressure.

This model is currently the most physiologically relevant model of AAA because it closely simulates many aspects of this disease in humans. The research was initiated by Iuliia Peshkova and Turan Aghayev, graduate students in Koltsova’s lab and study coauthors.

In their study, they assessed the role of IL-27 receptor signaling on the pathogenesis of AAA. They found that in contrast to what occurs in the development of atherosclerosis, mice that were deficient in IL-27 receptor were largely protected from angiotensin II-induced AAA.

“IL-27 receptor regulated bone marrow output, and if the mice did not have the IL-27 receptor there was no expansion of bone marrow and no production of immune cells that harm the aortic wall and drive aneurysm development,” Koltsova said.

“Our results suggest that IL-27 receptor signaling drives what we termed ‘stress myelopoiesis,’ which is induced by angiotensin II and is required for AAA progression,” Peshkova said.

According to Koltsova, similar inflammatory mechanisms are implicated in cardiovascular disease and cancer. For example, there are data suggesting that people who have had a myocardial infarction are more predisposed to cancer development.

Her lab continues to study the role of certain inflammatory mitigators of interest in both cardiovascular disease and cancer to gain a better understanding of how they work and whether their functions are applicable for treatment or cause a harmful effect. 

“Our finding that IL-27 receptor signaling is needed to regulate stress myelopoiesis and bone marrow output is important in AAA and in different malignancies,” Koltsova said. “Our research opens up a new direction in terms of understanding this receptor signaling in hematopoietic stem cells and eventually studying them in hematologic malignancies.”

The paper, “IL-27 Receptor-regulated Stress Myelopoiesis Drives Abdominal Aortic Aneurysm Development,” was published in Nature Communications.

The research was supported by National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA006927 to Fox Chase Cancer Center; by American Cancer Society RSG-18-195-01-DDC and Department of Defense W81XWH-18-1-0472; by American Heart Association SDG 13SDG14490059; WW Smith Charitable Trust; NIH R21 CA202396; and NIH R01 HL133669 grants.

       

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