The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions

Stellato, Mara; Dewenter, Matthias; Rudnik, Michał; Hukara, Amela; Özsoy, Çağla; Renoux, Florian; Pachera, Elena; Gantenbein, Felix; Seebeck, Petra; Uhtjaerv, Siim; Osto, Elena; Razansky, Daniel; Klingel, Karin; Henes, Joerg; Distler, Oliver; Błyszczuk, Przemysław; Kania, Gabriela

doi:10.1038/s42003-023-04534-6

Cited by 4 publications

(3 citation statements)

References 42 publications

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“…There is only one previous study that analyzed the association between Cxs and fibrosis related to SSc [ 43 ]. In their study, Stellato et al analyzed the myocardium of a Fosl-2-overexpressing mouse model of SSc and found disorganized distribution of both Cx40 and Cx43 in the myocardium of the SSc model compared to wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Connexin 37, 40, 43 and Pannexin 1 Expression in the Gastric Mucosa of Patients with Systemic Sclerosis

Pavic,

Ogorevc,

Boric

et al. 2023

Biomedicines

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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Although its pathogenesis is not fully understood, connexins (Cxs) and pannexins (Panx) could be involved in the process of fibrosis. We analyzed the protein expression of Cx37, Cx40, Cx43, and Panx1 in the gastric mucosa of patients with SSc and healthy volunteers, using immunofluorescence staining. Protein levels of Cx37 were slightly increased, while the levels of Cx40 were significantly decreased in the lamina propria of the gastric mucosa of SSc patients compared to the controls. The changes were proportional to SSc severity, with the most prominent changes found in patients with severe diffuse cutaneous SSc. No differences in Cx43 or Panx1 levels were found between the analyzed groups of samples. The lack of changes in Cx43 expression, which has been previously associated with fibrosis, could be due to the weak expression of Cx43 in the gastric mucosa in general. Further studies on full-thickness gastric biopsies containing muscle layers and animal SSc models are needed to fully elucidate the role of Cxs and Panxs in SSc-associated fibrosis.

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Section: Discussionmentioning

confidence: 99%

Connexin 37, 40, 43 and Pannexin 1 Expression in the Gastric Mucosa of Patients with Systemic Sclerosis

Pavic,

Ogorevc,

Boric

et al. 2023

Biomedicines

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“…These genes belong to the activator protein-1 (AP-1) transcription factor family, which is important for cardiomyocyte stress responses, cardiac inflammation and fibrosis. 31,32 Notably, the STAT3 binding motif was also highly enriched.…”

Section: Atac-seq Highlights Ap-1 Family Genesmentioning

confidence: 99%

“…The powerful enrichment of the AP-1 family of transcription factors following rmIL11 injection, seen in bulk RNA-seq, snRNA-seq and ATAC-seq was unexpected and likely has detrimental effects in the mouse heart 31,37 . AP-1 family activation is not immediately downstream of IL11:IL11RA:gp130 signalling and thus, the early IL11-stimulated activation of JAK/STAT3 likely primes CMs to upregulate, activate and respond to AP-1 transcription factors.…”

Section: Jak Inhibition Protects Against Il11-induced Cardiac Dysfunc...mentioning

confidence: 99%

Interleukin 11 therapy causes acute heart failure and its use in patients should be reconsidered

Sweeney,

O’Fee,

Villanueva-Hayes

et al. 2023

Preprint

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BackgroundInterleukin 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.MethodsWe 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.ResultsInjection 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.ConclusionsInjection 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 PerspectiveWhat is new?Injection of IL11 to mice causes acute and dose-dependent left ventricular impairmentIL11 activates JAK/STAT3 in cardiomyocytes to cause cell stress, inflammation and impaired calcium handlingThese data identify, for the first time, that IL11 is directly toxic in cardiomyocytes, overturning the earlier literature that suggested the oppositeWhat 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 effectsWe show that IL11 injection causes cardiomyocyte dysfunction and heart failure, which explains its cardiac toxicities that were previously thought non-specificThese findings have immediate translational implications as they question the continued use of rhIL11 in patients around the world

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Engineered model of heart tissue repair for exploring fibrotic processes and therapeutic interventions

Yang,

Zhu,

Wang

et al. 2024

Nat Commun

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The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions

Cited by 4 publications

References 42 publications

Connexin 37, 40, 43 and Pannexin 1 Expression in the Gastric Mucosa of Patients with Systemic Sclerosis

Connexin 37, 40, 43 and Pannexin 1 Expression in the Gastric Mucosa of Patients with Systemic Sclerosis

Interleukin 11 therapy causes acute heart failure and its use in patients should be reconsidered

Engineered model of heart tissue repair for exploring fibrotic processes and therapeutic interventions

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