Fibroblast-specific deletion of IL-1 receptor-1 reduces adverse cardiac remodeling following myocardial infarction
Sumia A. Bageghni, Karen E. Hemmings, Nadira Y. Yuldasheva, Azhar Maqbool, Filomena O. Gamboa-Esteves, Neil E. Humphreys, Maj Simonsen Jackson, Christopher P. Denton, Sheila Francis, Karen E. Porter, Justin F.X. Ainscough, Emmanuel Pinteaux, Mark J. Drinkhill, Neil A. Turner
Sumia A. Bageghni, Karen E. Hemmings, Nadira Y. Yuldasheva, Azhar Maqbool, Filomena O. Gamboa-Esteves, Neil E. Humphreys, Maj Simonsen Jackson, Christopher P. Denton, Sheila Francis, Karen E. Porter, Justin F.X. Ainscough, Emmanuel Pinteaux, Mark J. Drinkhill, Neil A. Turner
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Research Article Cardiology Inflammation

Fibroblast-specific deletion of IL-1 receptor-1 reduces adverse cardiac remodeling following myocardial infarction

Abstract

It has been hypothesized that IL-1α is released from damaged cardiomyocytes following myocardial infarction (MI) and activates cardiac fibroblasts via its receptor (IL-1R1) to drive the early stages of cardiac remodeling. This study aimed to definitively test this hypothesis using cell type–specific IL-1α and IL-1R1–KO mouse models. A floxed Il1a mouse was created and used to generate a cardiomyocyte-specific IL-1α–KO (MIL1AKO) mouse line. A tamoxifen-inducible fibroblast-specific IL-1R1 hemizygous KO (FIL1R1KO) mouse line was also generated. Mice underwent experimental MI (permanent left anterior descending coronary artery ligation), and cardiac function was determined 4 weeks later by conductance pressure-volume catheter analysis. Molecular markers of remodeling were evaluated at various time points by real-time RT-PCR and histology. MIL1AKO mice showed no difference in cardiac function or molecular markers of remodeling after MI compared with littermate controls. In contrast, FIL1R1KO mice showed improved cardiac function and reduced remodeling markers after MI compared with littermate controls. In conclusion, these data highlight a key role for the IL-1R1/cardiac fibroblast signaling axis in regulating remodeling after MI and provide support for the continued development of anti–IL-1 therapies for improving cardiac function after MI. Cardiomyocyte-derived IL-1α was not an important contributor to remodeling after MI in this model.

Authors

Sumia A. Bageghni, Karen E. Hemmings, Nadira Y. Yuldasheva, Azhar Maqbool, Filomena O. Gamboa-Esteves, Neil E. Humphreys, Maj Simonsen Jackson, Christopher P. Denton, Sheila Francis, Karen E. Porter, Justin F.X. Ainscough, Emmanuel Pinteaux, Mark J. Drinkhill, Neil A. Turner

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Figure 4

Effect of tamoxifen-induced fibroblast-specific IL-1R1 knockdown on cardiac fibroblast responses to IL-1.

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Effect of tamoxifen-induced fibroblast-specific IL-1R1 knockdown on card...
(A) Schematic showing loxP-targeted Cre-mediated deletion of exon 5 within the IL-1 receptor-1 gene, Il1r1. (B–E) Fibroblast cultures were established from hearts of Cre-negative (Ctrl; n = 7) and Cre-positive (fibroblast-specific IL-1 receptor 1 KO [FIL1R1KO]; n = 5) hemizygous Il1r1fl/– mice 6 weeks after tamoxifen injection. (B) qRT-PCR analysis of basal Il1r1 mRNA expression in cardiac fibroblasts from Ctrl and FIL1R1KO mice. **P < 0.01 for effect of KO (unpaired t test). (C) Cardiac fibroblasts with different genotypes were exposed to vehicle (control, C), IL-1α (IL-1), or TNF-α (TNF) for 30 minutes before immunoblotting to measure activation of p38 MAP kinase (phosphorylation; p-p38) or activation of IκB-α (proteasome-mediated degradation). β-Actin, loading control. Plots to the right depict densitometric analysis relative to β-actin normalized to lane 1 for control (white symbols) or IL-1 treatment (colored symbols). n = 2. (D and E) Cardiac fibroblasts were treated with vehicle (white boxes) or 1 ng/ml IL-1α (colored boxes) for 6 hours before measuring mRNA levels of Il6, Mmp3, and Mmp9 by qRT-PCR (D), and IL-6 secretion by ELISA (E). ***P < 0.001; **P < 0.01; *P < 0.05, NS, not significant for effect of IL-1; ##P < 0.01; #P < 0.05 for effect of IL-1R1 KO (2-way ANOVA with Bonferroni post hoc).