Cytokine mediated regulation of stress myelopoiesis in abdominal aortic aneurysm

细胞因子介导的腹主动脉瘤应激性骨髓生成的调节

• 批准号: 10523508
• 负责人: Ekaterina Koltsova
• 金额: $ 49.06万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523508
• 关键词: Abdominal Aortic Aneurysm; Affect; Age; Angiotensin II; Anti-Inflammatory Agents; Antibodies; Aorta; Apolipoprotein E; Area; Atherosclerosis; Automobile Driving; Biochemical; Biological; Biology; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular Pathology; Cause of Death; Cell Cycle; Cell Proliferation; Cells; Cellular Metabolic Process; Collaborations; Cytokine Signaling; Data; Development; Disease; Distal; Distant; Elderly; Exhibits; Family; Gender; Generations; Genetic Models; Genetic Predisposition to Disease; Hematopoiesis; Hematopoietic stem cells; Hypertension; IL27RA gene; IL6 gene; Immune; Immune mediated destruction; Immunologics; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-12; Interleukins; Knowledge; Life; Macrophage; Mediating; Methods; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Output; Oxidative Phosphorylation; Pathogenesis; Pathogenicity; Pathway interactions; Play; Population; Prevention; Preventive; Production; Regulation; Research; Risk Factors; Role; Scheme; Signal Transduction; Site; Smoking; Stimulus; Stress; System; TP53 gene; Therapeutic; Work; anaerobic glycolysis; cytokine; disorder prevention; fitness; hematopoietic stem cell expansion; hematopoietic stem cell quiescence; in vivo; innovation; insight; male; member; monocyte; neutrophil; novel; pharmacologic; programs; recruit; response; therapeutic development; transcriptomics; translational potential

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 and stress myelopoiesis in AAA development will open new avenues to study the relationship between the bone marrow response to the disease-relevant stimuli and cardiovascular pathology.

项目总结/文摘

项目成果

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma.

• DOI: 10.3390/ijms24087640
• 发表时间: 2023-04-21
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Ji, Jun Ho;Ha, Sang Yun;Lee, Danbi;Sankar, Kamya;Koltsova, Ekaterina K.;Abou-Alfa, Ghassan K.;Yang, Ju Dong
• 通讯作者: Yang, Ju Dong

Fat and inflammation: adipocyte-myeloid cell crosstalk in atherosclerosis.

• DOI: 10.3389/fimmu.2023.1238664
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Mazitova, Aleksandra M.;Marquez-Sanchez, Ana Cristina;Koltsova, Ekaterina K.
• 通讯作者: Koltsova, Ekaterina K.

Recent advances in the management of hepatocellular carcinoma.

• DOI: 10.3350/cmh.2023.0125
• 发表时间: 2024-01
• 期刊: Clinical and molecular hepatology
• 影响因子: 8.9
• 作者: Sankar K;Gong J;Osipov A;Miles SA;Kosari K;Nissen NN;Hendifar AE;Koltsova EK;Yang JD
• 通讯作者: Yang JD