# Cytokine mediated regulation of stress myelopoiesis in abdominal aortic aneurysm

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2021 · $507,368

## Abstract

PROJECT SUMMARY/ABSTRACT
Cardiovascular diseases are a major cause of death among “westernized” populations. One of the life-
threatening vascular conditions in the elderly is an asymptomatic formation of aortic abdominal aneurysm (AAA).
Immune-mediated destruction of the aortic wall during AAA plays a significant role in the pathogenesis of this
disease. Cytokines, soluble mediators of inflammation, contribute to immune cell accumulation and activation in
the affected area. While role of several cytokines in AAA was previously investigated, their proposed function
was limited to their action in the vessel wall. While inflammation and immune cells are implicated in the AAA, the
inflammatory mechanisms driving AAA initiation and progression are still poorly understood. For example,
whether (and how) cytokines and AngII signaling collaborate to produce and recruit pathogenic immune cells out
of bone marrow represents a major gap in knowledge.
 Interleukin (IL)27, a member of the IL6/IL12 family, is conventionally regarded as an anti-inflammatory
cytokine; however, the role of IL27R signaling in AAA has never been elucidated. Here we propose to investigate
the role of IL27R signaling in regulation of AAA development, and the mechanistic basis underlying its effect.
Using an established atherosclerosis-prone model predisposing to AAA (Apoe-/- mice) that combines a
susceptible genetic background with Angiotensin II mediated induction of disease, we made the unanticipated
observation that mice lacking IL27R signaling (IL27ra-/-) exhibited a remarkable reduction in the accumulation of
myeloid cells to the suprarenal aortas (the AAA disease site), and thus significantly reduced AAA incidence and
progression. Our preliminary data suggest that IL27R signaling is essential for the ability of AAA-inducing AngII
to drive hematopoietic stem cells (HSC) activation and stress induced myelopoiesis in the bone marrow, which
generates the AAA-promoting myeloid cells that are recruited to the disease site. These unanticipated findings
implicate IL27R signaling as a critical, targetable, pro-inflammatory mediator of AAA, and leads us to hypothesize
that IL27R signaling drives AAA by potentiating HSC fitness and differentiation toward myeloid lineages in
response to AngII. Mechanistically, we will determine: 1) how IL27R signaling regulates HSC “fitness,” activation
and “stress-induced” myeloid differentiation in AAA; and 2) the molecular and cellular mechanisms underlying
this unexpected connection, which will reveal whether IL27R may be leveraged as a significant target for AAA
prevention and therapy. We will do so by integrating an array of immunological, biochemical and molecular
biological methods. Overall, the proposed research will uncover the role of IL27R signaling in AAA development.
This work has translational potential and IL27R signaling may become an attractive candidate for preventive and
therapeutic approaches. Studies on the biology of IL27 within HSC...

## Key facts

- **NIH application ID:** 10305359
- **Project number:** 7R01HL149946-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Ekaterina Koltsova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,368
- **Award type:** 7
- **Project period:** 2019-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305359

## Citation

> US National Institutes of Health, RePORTER application 10305359, Cytokine mediated regulation of stress myelopoiesis in abdominal aortic aneurysm (7R01HL149946-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10305359. Licensed CC0.

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