白细胞介素-35 促进心肌梗死后小鼠巨噬细胞存活并改善伤口愈合。
Interleukin-35 Promotes Macrophage Survival and Improves Wound Healing After Myocardial Infarction in Mice.
机构信息
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.).
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.).
出版信息
Circ Res. 2019 Apr 26;124(9):1323-1336. doi: 10.1161/CIRCRESAHA.118.314569.
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 Ly6C and major histocompatibility complex II/C-C motif chemokine receptor type 2 (MHC II 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 Ly6C 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 CX3CR1Ly6C macrophage survival.
背景
靶向炎症已被证明能为心血管疾病领域带来临床获益。虽然调控调节性 T 细胞功能是免疫治疗的一个重要目标，但介导其抑制活性的分子在很大程度上仍是未知的。白细胞介素（IL）-35 是一种免疫抑制细胞因子，主要由调节性 T 细胞产生，是 IL-12 家族的一个新成员，由 EBI3（Epstein-Barr 病毒诱导基因 3）亚基和 p35 亚基组成。然而，IL-35 在梗死愈合中的作用仍不清楚。
目的
本研究旨在确定 IL-35 信号是否参与心肌梗死（MI）后的愈合和心脏重构，如果是，则阐明潜在的分子机制。
方法和结果
在 MI 后，IL-35 亚基（EBI3 和 p35）主要在调节性 T 细胞中表达上调。在抑制 IL-35 后，与野生型 MI 小鼠相比，小鼠的梗死愈合受损，心脏重构加重，死亡率因心脏破裂而显著增加，壁厚度降低，心功能恶化。IL-35 抑制还导致 MI 后小鼠心脏中 α-SMA（α-平滑肌肌动蛋白）和胶原 I/III 的表达减少。IL-35 的药理学抑制抑制了 Ly6C 和主要组织相容性复合体 II/C-C 基序趋化因子受体类型 2（MHC II CCR2）巨噬细胞在梗死心脏中的积累。IL-35 通过诱导 GP130 信号转导，通过 IL12Rβ2 和 STAT1（信号转导和转录激活因子家族）和 STAT4 的磷酸化，激活巨噬细胞中 CX3CR1（C-X3-C 基序趋化因子受体 1）和 TGFβ1（转化生长因子）的转录，随后促进 Ly6C 巨噬细胞的存活和细胞外基质的沉积。此外，与对照 MI 小鼠相比，IL-35 处理的 MI 小鼠的疤痕内α-SMA 和胶原表达增加，与左心室破裂率降低相关。
结论
IL-35 通过促进修复性 CX3CR1Ly6C 巨噬细胞存活，减少 MI 后的心脏破裂，改善伤口愈合，并减轻心脏重构。
Zotero 插件