Interleukin 11 therapy causes acute heart failure and its use in patients should be reconsidered
Authors: Sweeney Mark , O’Fee Katie , Villanueva-Hayes Chelsie , Rahman Ekhlas , Lee Michael , Maatz Henrike , Lindberg Eric L. , Vanezis Konstantinos , Andrew Ivan , Jennings Emma R. , Lim Wei-Wen , Widjaja Anissa A , Hubner Norbert , Barton Paul J.R. , Cook Stuart A 
Published: October 2023

Background

Interleukin 11 (IL11) was initially thought important for platelet production, which led to recombinant IL11 being developed as a drug to treat thrombocytopenia. IL11 was later found to be redundant for haematopoiesis and its use in patients is associated with unexplained cardiac side effects. Here we identify previously unappreciated and direct cardiomyocyte toxicities associated with IL11 therapy.

Methods

We injected recombinant mouse lL11 (rmIL11) into mice and studied its molecular effects in the heart using immunoblotting, qRT-PCR, bulk RNA-seq, single nuclei RNA-seq (snRNA-seq) and ATAC-seq. The physiological impact of IL11 was assessed by echocardiographyin vivoand using cardiomyocyte contractility assaysin vitro. To determine the activity of IL11 specifically in cardiomyocytes we made two cardiomyocyte-specificIl11ra1knockout mouse models using either AAV9-mediated andTnnt2-restricted (vCMKO) orMyh6(m6CMKO) Cre expression and anIl11ra1floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities.

Results

Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline (2 µL/kg), 60.4%±3.1; rmIL11 (200 mcg/kg), 31.6%±2.0; p<0.0001, n=5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed upregulation of pro-inflammatory pathways (TNFα, NFκB and JAK/STAT) and perturbed calcium handling. SnRNA-seq showed rmIL11-induced expression of stress factors (Ankrd1,Ankrd23,Xirp2), activator protein-1 (AP-1) transcription factor genes andNppbin the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified epigenetic enrichment of theAnkrd1andNppbgenes and stress-responsive, AP-1 transcription factor binding sites. Cardiomyocyte-specific effects were examined in vCMKO and m6CMKO mice, which were both protected from rmIL11-induced left ventricular impairment and molecular pathobiologies. In mechanistic studies, inhibition of JAK/STAT signalling with either ruxolitinib or tofacitinib prevented rmIL11-induced cardiac dysfunction.

Conclusions

Injection of IL11 directly activates JAK/STAT3 in cardiomyocytes to cause acute heart failure. Our data overturn the earlier assumption that IL11 is cardioprotective and explain the serious cardiac side effects associated with IL11 therapy, which questions its continued use in patients.

Clinical Perspective

What is new?

Injection of IL11 to mice causes acute and dose-dependent left ventricular impairment

IL11 activates JAK/STAT3 in cardiomyocytes to cause cell stress, inflammation and impaired calcium handling

These data identify, for the first time, that IL11 is directly toxic in cardiomyocytes, overturning the earlier literature that suggested the opposite

What are the clinical implications?

Recombinant human IL11 (rhIL11) is used as a drug to increase platelets in patients with thrombocytopenia but this has severe and unexplained cardiac side effects

We show that IL11 injection causes cardiomyocyte dysfunction and heart failure, which explains its cardiac toxicities that were previously thought non-specific

These findings have immediate translational implications as they question the continued use of rhIL11 in patients around the world