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Susceptibility to innate immune activation in genetically mediated myocarditis
Daniel F. Selgrade, … , Kathleen J. Green, Elizabeth M. McNally
Daniel F. Selgrade, … , Kathleen J. Green, Elizabeth M. McNally
Published May 20, 2024
Citation Information: J Clin Invest. 2024;134(13):e180254. https://doi.org/10.1172/JCI180254.
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Research Article Cardiology Inflammation

Susceptibility to innate immune activation in genetically mediated myocarditis

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Abstract

Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis. To model DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) from patients with heterozygous DSP truncating variants (DSPtvs) and a gene-edited homozygous deletion cell line (DSP–/–). At baseline, DSP–/– EHTs displayed a transcriptomic signature of innate immune activation, which was mirrored by cytokine release. Importantly, DSP–/– EHTs were hypersensitive to Toll-like receptor (TLR) stimulation, demonstrating more contractile dysfunction compared with isogenic controls. Relative to DSP–/– EHTs, heterozygous DSPtv EHTs had less functional impairment. DSPtv EHTs displayed heightened sensitivity to TLR stimulation, and when subjected to strain, DSPtv EHTs developed functional deficits, indicating reduced contractile reserve compared with healthy controls. Colchicine or NF-κB inhibitors improved strain-induced force deficits in DSPtv EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Thus, EHTs replicate electrical and contractile phenotypes seen in human myocarditis, implicating cytokine release as a key part of the myogenic susceptibility to inflammation. The heightened innate immune activation and sensitivity are targets for clinical intervention.

Authors

Daniel F. Selgrade, Dominic E. Fullenkamp, Ivana A. Chychula, Binjie Li, Lisa Dellefave-Castillo, Adi D. Dubash, Joyce Ohiri, Tanner O. Monroe, Malorie Blancard, Garima Tomar, Cory Holgren, Paul W. Burridge, Alfred L. George Jr., Alexis R. Demonbreun, Megan J. Puckelwartz, Sharon A. George, Igor R. Efimov, Kathleen J. Green, Elizabeth M. McNally

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Figure 6

Improved contractile function with NF-κB inhibition in DSP EHTs.

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Improved contractile function with NF-κB inhibition in DSP EHTs.
(A) Tre...
(A) Treatment with BAY 11-7082, an NF-κB inhibitor, improved fractional shortening of DSP p.E1597X and p.R1951X EHTs with no significant effect on healthy control cells (*< 0.05, **< 0.01 by 2-way ANOVA, n = 9–12 EHTs per condition, data representative of 3 batches). (B and C) BAY 11-7082 improved strain-induced force loss in DSP p.E1597X EHTs as measured in force time integral (B) and active force (C) (*< 0.05, **< 0.01 by 2-way ANOVA, n = 3–4 EHTs per condition across 2 batches, labeled as n1 = black dots, n2 = white dots, n3 = gray dots, n4 = brown dots). Box plots show the interquartile range, median (line), and minimum and maximum (whiskers). (D and E) Cytokine arrays of p.E1597X EHT media showed a significant reduction of baseline cytokine secretion following BAY 11-7082 treatment (†< 0.0001, ‡< 0.001, Δ< 0.01, ◊< 0.05 by 2-way ANOVA with n = 4 per condition). Data presented as individual recordings normalized to average baseline measurement per EHT. Significance calculated based on mean value per EHT.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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