Interleukin 11 therapy causes acute left ventricular dysfunction

Mark Sweeney; Katie O'Fee; Chelsie Villanueva-Hayes; Ekhlas Rahman; Michael Lee; Chung Nga Tam; Eneko Pascual-Navarro; Henrike Maatz; Eric L Lindberg; Konstantinos Vanezis; Chrishan J Ramachandra; Ivan Andrew; Emma R Jennings; Wei-Wen Lim; Anissa A Widjaja; David Carling; Derek J Hausenloy; Norbert Hubner; Paul J R Barton; Stuart A Cook

doi:10.1093/cvr/cvae224

Interleukin 11 therapy causes acute left ventricular dysfunction

Cardiovasc Res. 2024 Oct 9:cvae224. doi: 10.1093/cvr/cvae224. Online ahead of print.

Authors

Mark Sweeney^{1

2

3}, Katie O'Fee^{1

2}, Chelsie Villanueva-Hayes^{1

2}, Ekhlas Rahman^{1

2}, Michael Lee⁴, Chung Nga Tam¹, Eneko Pascual-Navarro^{1

2}, Henrike Maatz^{5

6}, Eric L Lindberg⁵, Konstantinos Vanezis^{1

2

4}, Chrishan J Ramachandra^{7

8}, Ivan Andrew^{1

2}, Emma R Jennings², Wei-Wen Lim^{7

8}, Anissa A Widjaja⁸, David Carling^{1

2}, Derek J Hausenloy^{7

8

9

10}, Norbert Hubner^{5

6

11}, Paul J R Barton^{1

2

4

12}, Stuart A Cook^{1

2

7

8}

Affiliations

¹ MRC-Laborary of Medical Sciences, Hammersmith Hospital Campus, London, UK.
² Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
³ Wellcome Trust/NIHR 4i Clinical Research Fellow, Imperial College London, London, UK.
⁴ National Heart and Lung Institute, Imperial College London, London, UK.
⁵ Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
⁶ DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
⁷ National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
⁸ Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore.
⁹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁰ The Hatter Cardiovascular Institute, University College London, London, UK.
¹¹ Charite, Universitätsmedizin Berlin, Berlin, Germany.
¹² Royal Brompton and Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, LondonUK.

PMID: 39383190
DOI: 10.1093/cvr/cvae224

Abstract

Aims: 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 and severe cardiac side effects. Here we aim to identify, for the first time, direct cardiomyocyte toxicities associated with IL11, which was previously believed cardioprotective.

Methods and results: 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 echocardiography in vivo and using cardiomyocyte contractility assays in vitro. To determine the activity of IL11 specifically in cardiomyocytes we made two cardiomyocyte-specific Il11ra1 knockout (CMKO) mouse models using either AAV9-mediated and Tnnt2-restricted (vCMKO) or Myh6 (m6CMKO) Cre expression and an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities. Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline: 62.4% ± 1.9; rmIL11: 32.6% ± 2.9, p<0.001, 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 and Nppb in the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified the Ankrd1 and Nppb genes and loci enriched for 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 IL11RA/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.