Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy.
BACKGROUND
One-third of myocarditis cases progresses to dilated cardiomyopathy (DCM), but the mechanisms controlling this process are largely unknown. CD4(+) T helper (Th)17 cells have been implicated in the pathogenesis of autoimmune diseases, but the role of Th17-produced cytokines during inflammation-induced cardiac remodeling has not been previously studied.


OBJECTIVE
We examined the importance of interleukin (IL)-17A in the progression of myocarditis to DCM using a mouse model.


RESULTS
Immunization of mice with myocarditogenic peptide in complete Freund's adjuvant induced the infiltration of IL-17A-producing Th17 cells into the inflamed heart. Unexpectedly, IL-17A-deficient mice developed myocarditis with similar incidence and severity compared to wild-type mice. Additionally, IL-17A deficiency did not ameliorate the severe myocarditis of interferon (IFN)gamma-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, IL-17A-deficient mice were protected from postmyocarditis remodeling and did not develop DCM. Flow cytometric and cytokine analysis revealed an important role for IL-17A in heart-specific upregulation of IL-6, TNFalpha, and IL-1beta and the recruitment of CD11b(+) monocyte and Gr1(+) granulocyte populations into the heart. Furthermore, IL-17A-deficient mice had reduced interstitial myocardial fibrosis, downregulated expression of matrix metalloproteinase-2 and -9 and decreased gelatinase activity. Treatment of BALB/c mice with anti-IL-17A monoclonal antibody administered after the onset of myocarditis abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function.


CONCLUSIONS
Our findings reveal a critical role for IL-17A in postmyocarditis cardiac remodeling and the progression to DCM. Targeting IL-17A may be an attractive therapy for patients with inflammatory dilated cardiomyopathy.
Baldeviano
G Christian
GC
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Barin
Jobert G
JG
Talor
Monica V
MV
Srinivasan
Sachin
S
Bedja
Djahida
D
Zheng
Dongfeng
D
Gabrielson
Kathleen
K
Iwakura
Yoichiro
Y
Rose
Noel R
NR
Cihakova
Daniela
D
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D009202:Cardiomyopathies / Q000503:physiopathology*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D007114:Immunization; D007249:Inflammation / Q000503:physiopathology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009205:Myocarditis / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology
D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D020381:Interleukin-17