Open AccessSTAT3 activity is necessary and sufficient for the development of immune‐mediated myocarditis in mice and promotes progression to dilated cardiomyopathy
Author(s) -
Camporeale Annalisa,
Marino Francesca,
Papageorgiou Anna,
Carai Paolo,
Fornero Sara,
Fletcher Steven,
Page Brent D. G.,
Gunning Patrick,
Forni Marco,
Chiarle Roberto,
Morello Mara,
Jensen Ole,
Levi Renzo,
Heymans Stephane,
Poli Valeria
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201876
Subject(s) - myocarditis , immunology , immune system , dilated cardiomyopathy , inflammation , medicine , pathogenesis , viral myocarditis , cardiomyopathy , complement system , heart failure
Myocarditis, often triggered by viral infection, may lead to heart auto‐immunity and dilated cardiomyopathy. What determines the switch between disease resolution and progression is however incompletely understood. We show that pharmacological inhibition of STAT3, the main mediator of IL‐6 signalling and of Th17‐cell differentiation, protects mice from the development of Experimental Auto‐immune Myocarditis reducing liver production of the complement component C3, and can act therapeutically when administered at disease peak. Further, we demonstrate that STAT3 is sufficient when constitutively active for triggering the onset of immune‐mediated myocarditis, involving enhanced complement C3 production and IL‐6 signalling amplification in the liver. Disease development can be prevented by C3 depletion and IL‐6 receptor neutralization. This appears to be relevant to disease pathogenesis in humans, since acute myocarditis patients display significantly elevated circulating IL‐6 and C3 levels and activated heart STAT3. Thus, aberrant IL‐6/STAT3‐mediated induction of liver acute phase response genes including C3, which occurs as a consequence of pre‐existing inflammatory conditions, might represent an important factor determining the degree of myocarditis and its clinical outcome.