Interleukin-11 (IL11) is a little studied member of the IL6 family that has gained increasing prominence in recent years as it has been identified as a key mediator of varied pathologies across multiple organ systems. The role that IL11 plays in myocardial function has been extensively debated, with much controversy, and remains unresolved.
In this thesis I use a combination of transgenic gain and loss of function mouse models, as well as direct administration of IL11 in vivo and ex vivo to investigate the effects of IL11 in the myocardium and specifically on cardiomyocytes. Using in vivo and ex vivo imaging tools I measure cardiomyocyte function and using a range of genomic approaches I characterise the myocardial transcriptional response to IL11. I proceed to analyse a range of mouse models of heart failure with preserved ejection fraction (HFpEF) to identify the role of IL11 in such models.
I demonstrate extensive profibrotic and proinflammatory changes in the myocardium in response to acute and chronic IL11 exposure. Direct effects of IL11 on cardiomyocytes impairs contractility and induces a stress response with increased expression of natriuretic peptides and the AP-1 family of transcription factors. IL11 does not appear to play an important role in the HFpEF models tested in this thesis but the models themselves were suboptimal and did not recapitulate the expected disease biology. I highlight future avenues in which anti-IL11 therapy may prove beneficial in the myocardium.
Overall, this thesis demonstrates the extensive proinflammatory, profibrotic and negatively inotropic effects of IL11 in the mouse myocardium and explains the cardiac side effect profile seen when IL11 is administered to humans. Understanding the cardiac biology of IL11 will inform future work to identify therapeutic opportunities for IL11 treatment in the heart, while also suggesting recombinant IL11 should no longer be administered to patients.