Type: Oral
Session: 503. Clonal Hematopoiesis, Aging, and Inflammation: Causes and Consequences
Hematology Disease Topics & Pathways:
Fundamental Science, Research, Diseases, Human, Study Population, Animal model
We modeled CH in mice by competitively transplanting whole bone marrow (WBM) cells deficient for Tet2, a frequently mutated CH gene, into irradiated WT recipient mice. Compared to mice transplanted with WT WBM, the Tet2–/– WBM recipients (“Tet2-CH” mice) exhibited cardiac dysfunction, as evidenced by an increased incidence of atrial fibrillation (AF) and reduced left ventricular ejection fraction, an indicator of heart failure. The Tet2-CH mice also had increased cardiac fibrosis and upregulation of the inflammasome signaling pathway, including the activation of Gasdermin D, the executor of pyroptosis. Remarkably, Gsdmd–/– recipient mice were protected from Tet2-CH-associated cardiac dysfunction and fibrosis.
Identifying the mechanisms that promote tissue fibrosis and inflammation in the context of CH is of significant therapeutic interest. We considered that Tet2–/– cells may lead to deleterious factors in the circulation. Using a multiplex cytokine array, we identified factors whose levels were preferentially elevated in the Tet2-CH model. Next, we identified those factors whose secretion was abrogated in Gsdmd–/– mice (compared to WT), under LPS-induced inflammatory stress. Among the handful of cytokines that satisfied both these criteria, interleukin-11 (IL-11) appeared to be the most interesting candidate.
IL-11 is a pleiotropic cytokine that is a master regulator of tissue fibrosis in organs such as the heart, liver, and kidneys. IL-11 is also upregulated with age and has recently emerged as a critical regulator of mammalian lifespan and health span. In addition to its upregulation in the Tet2-CH mouse model, serum IL-11 levels are elevated in aged WT mice and in a Dnmt3a-CH mouse model. This constellation of evidence encouraged us to determine whether abrogation of IL-11 signaling would mitigate CH-associated cardiac dysfunction. Indeed, administering an anti-IL-11 neutralizing antibody not only alleviated cardiac fibrosis but also ameliorated cardiac dysfunction in the Tet2-CH mouse model. We have elucidated that among all the major bone marrow cell types, only the stromal cells appreciably secrete IL-11, which they do in response to TGF-β produced by megakaryocytes. Furthermore, immunostaining of femur sections revealed that megakaryocyte numbers were elevated in the Tet2-CH mouse model suggesting a mechanism for the elevated serum IL-11 levels in Tet2-CH mice.
To determine the impact of circulating IL-11 levels on the incidence of cardiac dysfunction in humans, we analyzed the UK Biobank. After excluding people with preexisting cardiovascular disease or missing values, we constructed 2 cohorts with non-overlapping participants: those with IL-11 measured by the Olink platform (n=45,617) and those with genetically predicted IL-11 levels (n=395,385). Stratification of participants in these cohorts into tertiles based on either their measured IL-11 levels or predicted IL-11 levels, respectively, revealed that those with elevated IL-11 levels were associated with a higher incidence of CH-associated AF, but not non-CH-associated AF.
In conclusion, we developed a Tet2-CH mouse model that exhibits cardiac dysfunction and fibrosis, which can be reversed by ablating Gasdermin D. We identify IL-11 signaling as a novel driver of CH-associated cardiac dysfunction. Antibody blockade of IL-11 signaling ameliorates fibrosis and cardiac dysfunction. Analysis of UK Biobank data underscores the pathogenic role of IL-11 signaling in humans with CH. Due to its roles as a master regulator of tissue fibrosis and as an activator of inflammasome signaling, targeting IL-11 signaling could serve as an attractive therapeutic intervention for CH-associated pathologies.
Disclosures: Ballantyne: 89Bio, Abbott Diagnostics, Amarin, Amgen, Arrowhead, Astra Zeneca, Denka Seiken, Esperion, Genentech, Illumina, Ionis, Eli Lilly, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic: Consultancy; Abbott Diagnostic, Akcea, Amgen, Arrowhead, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic: Research Funding; TenSixteen Bio: Consultancy. Honigberg: CRISPR Therapeutics: Consultancy; Miga Health: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Natarajan: Vertex Pharmaceuticals: Other: Spousal employment; Eli Lilly & Co: Consultancy; Magnetic Biomedicine: Consultancy; Esperion Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blackstone Life Sciences: Consultancy; TenSixteen Bio: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Preciseli: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Allelica: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Creative Education Concepts: Consultancy; MyOme: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Foresite Labs: Consultancy; GV: Consultancy; Merk: Consultancy; HeartFlow: Consultancy.
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