IL-11 Signaling Drives Clonal Hematopoiesis-Associated Cardiac Dysfunction

Age-related acquisition of somatic mutations in hematopoietic stem cells leading to their clonal expansion gives rise to the preleukemic condition known as clonal hematopoiesis (CH). In addition to increasing the predisposition for hematological malignancies, CH is also associated with elevated risk for aging-associated disorders including cardiovascular disease, chronic liver disease, kidney disease, and others. Here, we aim to uncover a general molecular mechanism underlying CH-associated pathologies using CH-associated cardiac dysfunction as a paradigm.

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.

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.