Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation.
We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45(+) leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1beta, IL-18, interferon-gamma, transforming growth factor-beta1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4(+) T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4(+)CD25(+)Foxp3(+) regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206(+) and CD204(+) macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1beta and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.
Cihakova
Daniela
D
Johns Hopkins University, Department of Pathology, Division of Immunology, Ross 648, 720 Rutland Ave., Baltimore, MD 21205, USA. dcihako1@jhmi.edu
Barin
Jobert G
JG
Afanasyeva
Marina
M
Kimura
Miho
M
Fairweather
DeLisa
D
Berg
Michael
M
Talor
Monica V
MV
Baldeviano
G Christian
GC
Frisancho
Sylvia
S
Gabrielson
Kathleen
K
Bedja
Djahida
D
Rose
Noel R
NR
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002311:Cardiomyopathy, Dilated / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D003384:Coxsackievirus Infections / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D018793:Interleukin-13