Th2 regulation of viral myocarditis in mice: different roles for TLR3 versus TRIF in progression to chronic disease.
Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
Eric D
ED
Abston
Michael J
MJ
Coronado
Adriana
A
Bucek
Djahida
D
Bedja
Jaewook
J
Shin
Joseph B
JB
Kim
Eunyong
E
Kim
Kathleen L
KL
Gabrielson
Dimitrios
D
Georgakopoulos
Wayne
W
Mitzner
DeLisa
D
Fairweather
D000208:Acute Disease; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002908:Chronic Disease; D003384:Coxsackievirus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D018450:Disease Progression; D004770:Enterovirus / Q000472:pathogenicity / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D018418:Th2 Cells / Q000276:immunology / Q000821:virology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication
D033942:Adaptor Proteins, Vesicular Transport; D000067596:Interleukin-33; D015847:Interleukin-4; D007378:Interleukins; D051196:Toll-Like Receptor 3; C506535:Il33 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse