Daile Jia1,2,3,4, Hao Jiang1,2,3,4, Xinyu Weng1,2,3,4,5, Jian Wu1,2,3,4,5, Peiyuan Bai6, Wenlong Yang1,2,3,4, Zeng Wang1,2,3,4,5, Kai Hu1,2,3,4, Aijun Sun1,2,3,4,5, Junbo Ge1,2,3,4,5. 1. From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.). 2. Shanghai Institute of Cardiovascular Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.). 3. NHC Key Laboratory of Viral Heart Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.). 4. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.). 5. Institutes of Biomedical Sciences, Fudan University, Shanghai, China (X.W., J.W., Z.W., A.S., J.G.). 6. Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China (P.B.).
Abstract
RATIONALE: Targeting inflammation has been shown to provide clinical benefit in the field of cardiovascular diseases. Although manipulating regulatory T-cell function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. IL (interleukin)-35, an immunosuppressive cytokine mainly produced by regulatory T cells, is a novel member of the IL-12 family and is composed of an EBI3 (Epstein-Barr virus-induced gene 3) subunit and a p35 subunit. However, the role of IL-35 in infarct healing remains elusive. OBJECTIVE: This study aimed to determine whether IL-35 signaling is involved in healing and cardiac remodeling after myocardial infarction (MI) and, if so, to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: IL-35 subunits (EBI3 and p35), which are mainly expressed in regulatory T cells, were upregulated in mice after MI. After IL-35 inhibition, mice showed impaired infarct healing and aggravated cardiac remodeling, as demonstrated by a significant increase in mortality because of cardiac rupture, decreased wall thickness, and worse cardiac function compared with wild-type MI mice. IL-35 inhibition also led to decreased expression of α-SMA (α-smooth muscle actin) and collagen I/III in the hearts of mice after MI. Pharmacological inhibition of IL-35 suppressed the accumulation of Ly6Clow and major histocompatibility complex IIlow/C-C motif chemokine receptor type 2- (MHC IIlow CCR2-) macrophages in infarcted hearts. IL-35 activated transcription of CX3CR1 (C-X3-C motif chemokine receptor 1) and TGF (transforming growth factor) β1 in macrophages by inducing GP130 signaling, via IL12Rβ2 and phosphorylation of STAT1 (signal transducer and activator of transcription family) and STAT4 and subsequently promoted Ly6Clow macrophage survival and extracellular matrix deposition. Moreover, compared with control MI mice, IL-35-treated MI mice showed increased expression of α-SMA and collagen within scars, correlating with decreased left ventricular rupture rates. CONCLUSIONS: IL-35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling after MI by promoting reparative CX3CR1+Ly6Clow macrophage survival.
RATIONALE: Targeting inflammation has been shown to provide clinical benefit in the field of cardiovascular diseases. Although manipulating regulatory T-cell function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. IL (interleukin)-35, an immunosuppressive cytokine mainly produced by regulatory T cells, is a novel member of the IL-12 family and is composed of an EBI3 (Epstein-Barr virus-induced gene 3) subunit and a p35 subunit. However, the role of IL-35 in infarct healing remains elusive. OBJECTIVE: This study aimed to determine whether IL-35 signaling is involved in healing and cardiac remodeling after myocardial infarction (MI) and, if so, to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: IL-35 subunits (EBI3 and p35), which are mainly expressed in regulatory T cells, were upregulated in mice after MI. After IL-35 inhibition, mice showed impaired infarct healing and aggravated cardiac remodeling, as demonstrated by a significant increase in mortality because of cardiac rupture, decreased wall thickness, and worse cardiac function compared with wild-type MI mice. IL-35 inhibition also led to decreased expression of α-SMA (α-smooth muscle actin) and collagen I/III in the hearts of mice after MI. Pharmacological inhibition of IL-35 suppressed the accumulation of Ly6Clow and major histocompatibility complex IIlow/C-C motif chemokine receptor type 2- (MHC IIlow CCR2-) macrophages in infarcted hearts. IL-35 activated transcription of CX3CR1 (C-X3-C motif chemokine receptor 1) and TGF (transforming growth factor) β1 in macrophages by inducing GP130 signaling, via IL12Rβ2 and phosphorylation of STAT1 (signal transducer and activator of transcription family) and STAT4 and subsequently promoted Ly6Clow macrophage survival and extracellular matrix deposition. Moreover, compared with control MI mice, IL-35-treated MI mice showed increased expression of α-SMA and collagen within scars, correlating with decreased left ventricular rupture rates. CONCLUSIONS: IL-35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling after MI by promoting reparative CX3CR1+Ly6Clow macrophage survival.
Authors: Dawn M Fernandez; Adeeb H Rahman; Nicolas F Fernandez; Aleksey Chudnovskiy; El-Ad David Amir; Letizia Amadori; Nayaab S Khan; Christine K Wong; Roza Shamailova; Christopher A Hill; Zichen Wang; Romain Remark; Jennifer R Li; Christian Pina; Christopher Faries; Ahmed J Awad; Noah Moss; Johan L M Bjorkegren; Seunghee Kim-Schulze; Sacha Gnjatic; Avi Ma'ayan; J Mocco; Peter Faries; Miriam Merad; Chiara Giannarelli Journal: Nat Med Date: 2019-10-07 Impact factor: 53.440