Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation.
BACKGROUND
An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3(+) CD4(+) regulatory T cells (Treg cells) contribute to inflammation resolution. Therefore, Treg cells might influence cardiac healing post-MI.


OBJECTIVE
Our aim was to study the functional role of Treg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation.


RESULTS
Using a model of genetic Treg-cell ablation (Foxp3(DTR) mice), we depleted the Treg-cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, Treg-cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in Treg-cell-ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody-mediated depletion. In contrast, therapeutic Treg-cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA-treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic Treg-cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing.


CONCLUSIONS
Our data indicate that Treg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of Treg cells constitutes a novel approach to improve healing post-MI.
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Johannes
J
Weirather
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany. hofmann_u2@klinik.uni-wuerzburg.de.
Ulrich D W
UD
Hofmann
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Niklas
N
Beyersdorf
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Gustavo C
GC
Ramos
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Benjamin
B
Vogel
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Anna
A
Frey
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Georg
G
Ertl
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Thomas
T
Kerkau
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
Stefan
S
Frantz
D000818:Animals; D002454:Cell Differentiation; D016764:Cell Polarity; D051858:Forkhead Transcription Factors / Q000502:physiology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D022423:Myeloid Cells / Q000502:physiology; D009203:Myocardial Infarction / Q000276:immunology / Q000503:physiopathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*; D014945:Wound Healing
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
myocardial infarction; wound healing