Macrophage-Derived mir-155-Containing Exosomes Suppress Fibroblast Proliferation and Promote Fibroblast Inflammation during Cardiac Injury

Abstract

Inflammation plays an important role in cardiac injuries. Here, we examined the role of miRNA in regulating inflammation and cardiac injury during myocardial infarction. We showed that mir-155 expression was increased in the mouse heart after myocardial infarction. Upregulated mir-155 was primarily presented in macrophages and cardiac fibroblasts of injured hearts, while pri-mir-155 was only expressed in macrophages. mir-155 was also presented in exosomes derived from macrophages, and it can be transferred into cardiac fibroblasts by macrophagederived exosomes. A mir-155 mimic or mir-155 containing exosomes inhibited cardiac fibroblast proliferation by downregulating Son of Sevenless 1 expression and promoted inflammation by decreasing Suppressor of Cytokine Signaling 1 expression. These effects were reversed by the addition of a mir-155 inhibitor. In vivo, mir-155-deficient mice showed a significant reduction of the incidence of cardiac rupture and an improved cardiac function compared with wild-type mice. Moreover, transfusion of wild-type macrophage exosomes to mir-155 À/À mice exacerbated cardiac rupture. Finally, the mir-155-deficient mice exhibited elevated fibroblast proliferation and collagen production, along with reduced cardiac inflammation in injured heart. Taken together, our results demonstrate that activated macrophages secrete mir-155-enriched exosomes and identify macrophagederived mir-155 as a paracrine regulator for fibroblast proliferation and inflammation; thus, a mir-155 inhibitor (i.e., mir-155 antagomir) has the potential to be a therapeutic agent for reducing acute myocardial-infarction-related adverse events.

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

“…Furthermore, miR-126 circulating in plasma has been proposed as a diagnostic marker for myocardial infarction [114]. An additional miRNA, miR-155, was elevated in cardiac macrophages in injured hearts, and its upregulation had a direct impact on fibroblast proliferation in post-MI remodeling [197]. The depletion of miR-155 in macrophages is correlated with decreased levels of CCL2, a chemokine that recruits monocytes, suggesting that macrophage-derived miR-155 expression might serve as a therapeutic target which could suppress both fibrosis and inflammatory responses [135].…”

“…This suggests that miRNA-155 might serve as a prognostic marker for cardiac death in post-MI patients [123]. miR-155 is also found in exosomes released by macrophages and this has effects on fibroblasts, which in turn trigger a dysregulation of fibrosis [197]. miR-155 is mainly involved in B- and T-cell receptor signaling, neurotrophin signaling, MAPK signaling, and the cell cycle.…”

“…miR-155 is mainly involved in B- and T-cell receptor signaling, neurotrophin signaling, MAPK signaling, and the cell cycle. Especially in regard to the cell-cycle signaling pathway, Sos1 expression is increased in the absence of miR-155, and is associated with fibroblast proliferation post-MI [197]. Also, angiotensin II-induced expression of the angiotensin II type 1 receptor (AT1R) and extracellular signal-related kinase 1/2 (ERK1/2) are downregulated by miR-155 [123].…”

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

“…These results were viewed as evidence that CDC exosomes may switch inert fibroblasts to cells that contribute to cardiac repair. Most recently, Wang et al (55) reported that macrophage-derived exosomes containing mir-155 suppressed fibroblast proliferation and promoted fibroblast inflammation during cardiac injury. Collectively, these findings suggest that exosomes may modify cardiac repair via modulation of fibroblast function.…”

MicroRNA as a Therapeutic Target in Cardiac Remodeling

“…miR-155 also promotes macrophage survival by upregulating the SHIP1-Akt signaling cascade [143]. The increased level of macrophage derived miR-155 acts as paracrine regulator of cardiac fibroblast proliferation as well as inflammatory response following the myocardial infarction induced injury [144]. In contrast, another research group found that miR-155 functions as a negative feedback regulator of immune response by reducing the expression of cytokines by cardiac myocytes during viral infection induced myocarditis [145].…”