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IL1RAP Blockade with a Monoclonal Antibody Reduces Cardiac Inflammation and Preserves Heart Function in Viral and Autoimmune Myocarditis

Lema, Diego A. ; Jakobsson, Gabriel LU ; Daoud, Abdel ; Elias, David ; Talor, Monica V. ; Rattik, Sara LU ; Grönberg, Caitríona LU ; Kalinoski, Hannah ; Jaensson Gyllenbäck, Elin LU and Wang, Nadan , et al. (2024) In Circulation: Heart Failure 17(12).
Abstract

BACKGROUND: Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone. METHODS: We induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by... (More)

BACKGROUND: Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone. METHODS: We induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by echocardiography. We used spatial transcriptomics (Visium 10× Genomics) to compare the gene expression landscape in the hearts of mCAN10-treated versus control mice. RESULTS: IL1RAP blockade reduced CVB3 and EAM severity. In EAM, the treatment prevented deterioration of cardiac function, measured on day 42 post-disease induction (left ventricular ejection fraction: 56.5% versus 51.0% in isotype controls [P=0.002] and versus 51.4% in mice treated with anti-IL-1β antibodies alone [P=0.003]; n=10-11 mice per group). In the CVB3 model, mCAN10 did not impede viral clearance from the heart and significantly lowered the numbers of CD4+ (cluster of differentiation 4) T cells (P=0.025), inflammatory Ly6C+CCR2+ (lymphocyte antigen 6 complex, locus C/C-C motif chemokine receptor 2) monocytes (P=0.038), neutrophils (P=0.001) and eosinophils (P<0.001) infiltrating the myocardium. The spatial transcriptomic analysis revealed reduced canonical IL-1 signaling and chemokine expression in cardiac immune foci in CVB3-infected mice treated with IL1RAP blockade. CONCLUSIONS: Blocking IL1RAP reduces acute CVB3 myocarditis and EAM severity and preserves cardiac function in EAM. We conclude that IL1RAP blockade is a potential therapeutic strategy in viral and autoimmune myocarditis.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
eosinophils, flow cytometry, monocytes, myocarditis, therapeutics
in
Circulation: Heart Failure
volume
17
issue
12
article number
e011729
publisher
American Heart Association
external identifiers
  • pmid:39513273
  • scopus:85209245928
ISSN
1941-3289
DOI
10.1161/CIRCHEARTFAILURE.124.011729
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 The Authors. Circulation: Heart Failure is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc.
id
573ff25a-9300-4cc2-a695-9a00a92db21a
date added to LUP
2025-01-23 11:50:34
date last changed
2025-03-06 14:38:19
@article{573ff25a-9300-4cc2-a695-9a00a92db21a,
  abstract     = {{<p>BACKGROUND: Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone. METHODS: We induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by echocardiography. We used spatial transcriptomics (Visium 10× Genomics) to compare the gene expression landscape in the hearts of mCAN10-treated versus control mice. RESULTS: IL1RAP blockade reduced CVB3 and EAM severity. In EAM, the treatment prevented deterioration of cardiac function, measured on day 42 post-disease induction (left ventricular ejection fraction: 56.5% versus 51.0% in isotype controls [P=0.002] and versus 51.4% in mice treated with anti-IL-1β antibodies alone [P=0.003]; n=10-11 mice per group). In the CVB3 model, mCAN10 did not impede viral clearance from the heart and significantly lowered the numbers of CD4+ (cluster of differentiation 4) T cells (P=0.025), inflammatory Ly6C+CCR2+ (lymphocyte antigen 6 complex, locus C/C-C motif chemokine receptor 2) monocytes (P=0.038), neutrophils (P=0.001) and eosinophils (P&lt;0.001) infiltrating the myocardium. The spatial transcriptomic analysis revealed reduced canonical IL-1 signaling and chemokine expression in cardiac immune foci in CVB3-infected mice treated with IL1RAP blockade. CONCLUSIONS: Blocking IL1RAP reduces acute CVB3 myocarditis and EAM severity and preserves cardiac function in EAM. We conclude that IL1RAP blockade is a potential therapeutic strategy in viral and autoimmune myocarditis.</p>}},
  author       = {{Lema, Diego A. and Jakobsson, Gabriel and Daoud, Abdel and Elias, David and Talor, Monica V. and Rattik, Sara and Grönberg, Caitríona and Kalinoski, Hannah and Jaensson Gyllenbäck, Elin and Wang, Nadan and Liberg, David and Schiopu, Alexandru and Čiháková, Daniela}},
  issn         = {{1941-3289}},
  keywords     = {{eosinophils; flow cytometry; monocytes; myocarditis; therapeutics}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  publisher    = {{American Heart Association}},
  series       = {{Circulation: Heart Failure}},
  title        = {{IL1RAP Blockade with a Monoclonal Antibody Reduces Cardiac Inflammation and Preserves Heart Function in Viral and Autoimmune Myocarditis}},
  url          = {{http://dx.doi.org/10.1161/CIRCHEARTFAILURE.124.011729}},
  doi          = {{10.1161/CIRCHEARTFAILURE.124.011729}},
  volume       = {{17}},
  year         = {{2024}},
}