Inflammatory dilated cardiomyopathy (DCMI) is among the most common causes of heart failure in individuals under the age of 40. Our finding that IL17A is critical for the progression from myocarditis to DCMI has led to the discovery of a novel immunological pathway that drives DCMI. Specifically, IL17A signaling induces GMCSF production from cardiac fibroblasts. GM-CSF then drives differentiation of cardiac infiltrating MO/M? toward Ly6Chi inflammatory MO/M?, which in turn promotes DCMI. We propose targeting this pathway to prevent and treat DCMI. Our overall hypothesis is that IL17A drives DCMI by promoting the expansion of Ly6Chi inflammatory MO/M? in trans through cardiac fibroblast-derived GM-CSF.
In Aim 1 we will investigate the role of cardiac fibroblasts in IL17A-driven DCMI. Using chimeric mice lacking IL17RA in either the hematopoietic or cardiac-resident compartment we found that IL17 signaling in cardiac-resident cells are essential for DCMI. Cardiac fibroblasts produce high levels of GM-CSF in response to IL17A. GM-CSF expression by cardiac fibroblasts in vivo was at its maximum at the peak of cardiac infiltration at day 21 of EAM. To directly address the importance of IL17A signaling in cardiac fibroblasts for the development of DCMI in vivo, we will employ conditional knockouts that specifically ablate IL17 signaling in fibroblasts using transgenic Cre expression under the control of the promoter of the calcium-binding protein FSP1 (S100a4) (Subaim 1.1). Next, in Subaim 1.2 we will examine if the overexpression of GM-CSF by cardiac-resident cells using adeno-associated virus vector under the cardiac troponin promoter will result in an accumulation of Ly6Chi inflammatory MO/M? in the heart and accelerated DCMI.
In Aim 2, we will study IL17A-driven pathways of cardiac fibroblasts communication to inflammatory MO/M?. In vitro IL17A-stimulated cardiac fibroblasts produce large amounts of GM-CSF, which drives the differentiation of MO/M? towards a Ly6Chi inflammatory phenotype. We will investigate the role of in vitro generated inflammatory MO/M? by transferring these cells into mice with EAM. We expect that this transfer will exacerbate DCMI in WT mice (Subaim 2.1), and restore susceptibility to DCMI in IL17RA-/- mice (Subaim 2.2).
In Aim 3, we will explore the therapeutic potential of depleting Ly6Chi inflammatory MO/M? to arrest DCMI. We will employ two strategies to directly target inflammatory MO/M? in the heart. First, we will decrease the number of Ly6Chi inflammatory MO/M? in the heart by converting them to resident MO/M? through the phagocytosis of liposomes (Subaim 3.1). Second, we will arrest Ly6Chi inflammatory MO/M? trafficking to the heart by silencing CCR2 using dendrimer-siRNA complexes (Subaim 3.2). In summary, we have discovered a novel immunological pathway through which IL17A induces GM-CSF production by cardiac fibroblasts, leading to the accumulation of Ly6Chi inflammatory MO/M? in the heart, which then promote DCMI. These findings support specific targeting of this pathway to prevent or arrest cardiac remodeling and DCMI.

Public Health Relevance

Dilated cardiomyopathy is a major cause of heart failure in individuals below the age of 40, and a major indication for cardiac transplantation. We propose to explore in depth the role of monocyte and macrophages in the development of dilated cardiomyopathy and search for novel approaches to treat and prevent this life-threatening disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL118183-04
Application #
9207487
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Adhikari, Bishow B
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
4
Fiscal Year
2017
Total Cost
$405,000
Indirect Cost
$155,000
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Diny, Nicola L; Rose, Noel R; ?iháková, Daniela (2017) Eosinophils in Autoimmune Diseases. Front Immunol 8:484
Bracamonte-Baran, William; ?iháková, Daniela (2017) Cardiac Autoimmunity: Myocarditis. Adv Exp Med Biol 1003:187-221
Barin, Jobert G; Talor, Monica V; Diny, Nicola L et al. (2017) Regulation of autoimmune myocarditis by host responses to the microbiome. Exp Mol Pathol 103:141-152
Diny, Nicola L; Hou, Xuezhou; Barin, Jobert G et al. (2016) Macrophages and cardiac fibroblasts are the main producers of eotaxins and regulate eosinophil trafficking to the heart. Eur J Immunol 46:2749-2760
Barin, Jobert G; Talor, Monica V; Schaub, Julie A et al. (2016) Collaborative Interferon-? and Interleukin-17 Signaling Protects the Oral Mucosa from Staphylococcus aureus. Am J Pathol 186:2337-52

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