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

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: 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 (D2KO) mice showed an improvement in the infarct healing and cardiac remodeling, compared with WT mice, which was demonstrated by significantly lower mortality due to cardiac rupture, increased wall thickness, and better cardiac function. Increased expression of α-smooth muscle actin (α-SMA), and collagen I/III was observed, while the levels of MMP2 and MMP9 were decreased in the hearts of D2KO 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 IL-12 production in the heart. Interferon-γ was shown to downregulate TGF-β-induced expression of α-SMA and collagen I/III in isolated cardiac fibroblasts, leading to a decrease in migration and myofibroblast differentiation. Lastly, 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.