Dectin-2 Deficiency Modulates Th1 Differentiation and Improves Wound Healing After Myocardial Infarction

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Abstract

Rationale:

Macrophages are involved in wound healing after myocardial infarction (MI). The role of Dectin-2, a pattern recognition receptor mainly expressed on myeloid cells, in the infarct healing remains unknown.

Objective:

The aim of this study is to determine whether Dectin-2 signaling is involved in the healing process and cardiac remodeling after MI and to elucidate the underlying molecular mechanisms.

Methods and Results:

In a mouse model of permanent coronary ligation, Dectin-2, mainly expressed in macrophages, was shown to be increased in the early phase after MI. Dectin-2 knockout mice showed an improvement in the infarct healing and cardiac remodeling, compared with wild-type mice, which was demonstrated by significantly lower mortality because of cardiac rupture, increased wall thickness, and better cardiac function. Increased expression of α-smooth muscle actin and collagen I/III was observed, whereas the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were decreased in the hearts of Dectin-2 knockout mice after MI. Dectin-2 deficiency inhibited the rate of apoptotic and necrotic cell death. However, Dectin-2 did not affect immune cell infiltration and macrophage polarization, but it led to a stronger activation of the Th1/interferon-γ immune reaction, through the enhancement of interleukin-12 production in the heart. Interferon-γ was shown to downregulate transforming growth factor-β–induced expression of α-smooth muscle actin and collagen I/III in isolated cardiac fibroblasts, leading to a decrease in migration and myofibroblast differentiation. Finally, Dectin-2 knockout improved myocardial ischemia–reperfusion injury and infarct healing.

Conclusions:

Dectin-2 leads to an increase in cardiac rupture, impairs wound healing, and aggravates cardiac remodeling after MI through the modulation of Th1 differentiation.

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