Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction.
Ischemic heart disease resulting from myocardial infarction (MI) is the most prevalent form of heart disease in the United States. Post-MI cardiac remodeling is a multifaceted process that includes activation of fibroblasts and a complex immune response. T-regulatory cells (Tregs), a subset of CD4+ T cells, have been shown to suppress the innate and adaptive immune response and limit deleterious remodeling following myocardial injury. However, the mechanisms by which injured myocardium recruits suppressive immune cells remain largely unknown. Here, we have shown a role for Hippo signaling in the epicardium in suppressing the post-infarct inflammatory response through recruitment of Tregs. Mice deficient in epicardial YAP and TAZ, two core Hippo pathway effectors, developed profound post-MI pericardial inflammation and myocardial fibrosis, resulting in cardiomyopathy and death. Mutant mice exhibited fewer suppressive Tregs in the injured myocardium and decreased expression of the gene encoding IFN-γ, a known Treg inducer. Furthermore, controlled local delivery of IFN-γ following MI rescued Treg infiltration into the injured myocardium of YAP/TAZ mutants and decreased fibrosis. Collectively, these results suggest that epicardial Hippo signaling plays a key role in adaptive immune regulation during the post-MI recovery phase.
Vimal
V
Ramjee
Deqiang
D
Li
Lauren J
LJ
Manderfield
Feiyan
F
Liu
Kurt A
KA
Engleka
Haig
H
Aghajanian
Christopher B
CB
Rodell
Wen
W
Lu
Vivienne
V
Ho
Tao
T
Wang
Li
L
Li
Anamika
A
Singh
Dasan M
DM
Cibi
Jason A
JA
Burdick
Manvendra K
MK
Singh
Rajan
R
Jain
Jonathan A
JA
Epstein
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018797:Cell Cycle Proteins; D005355:Fibrosis; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010496:Pericardium / Q000276:immunology* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse