BMP-7 Treatment Increases M2 Macrophage Differentiation and Reduces Inflammation and Plaque Formation in Apo E-/- Mice

Abstract

Inflammation plays a fundamental role in the inception and development of atherosclerosis (ATH). Mechanisms of inflammation include the infiltration of monocytes into the injured area and subsequent differentiation into either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. We have previously published data suggesting bone morphogenetic protein-7 (BMP-7) enhances M2 macrophage differentiation and anti-inflammatory cytokine secretion in vitro. In this regard, we hypothesized BMP-7 would inhibit plaque formation in an animal model of ATH through monocytic plasticity mediation. ATH was generated in male and female Apo E-/- mice via partial left carotid artery (PLCA) ligation and mice were divided into 3 groups: Sham, PLCA, and PLCA+BMP-7 (200ug/kg; i.v.). Our data suggest that BMP-7 inhibits plaque formation and increases arterial systolic velocity. Furthermore, we report inhibition of monocyte infiltration and a decrease in associated pro-inflammatory cytokines (MCP-1, TNF-α, and IL-6) in the PLCA+BMP-7 mice. In contrast, our data suggest a significant (p<0.05) increase in M2 macrophage populations with consequential enhanced anti-inflammatory cytokine (IL-1RA, IL-10, and Arginase 1) expression following BMP-7 treatment. We have also observed that mechanisms promoting monocyte into M2 macrophage differentiation by BMP-7 involve the upregulation and activation of the BMP-7 receptor (BMP-7RII). In conclusion, we report that BMP-7 has the potential to mediate cellular plasticity and mitigate the inflammatory immune response, which results in decreased plaque formation and improved blood velocity.

Microglia activation is essential for BMP7-mediated retinal reactive gliosis

“…BMP6 regulates expression of inflammatory markers such as IL-6, IL-1β, and nitric oxide synthase in macrophages [78–80]. In addition, more recent studies indicate that BMP exposure particularly leads to the M2 or anti-inflammatory phenotype of the macrophages promoting tissue repair [81–84]. Microglia are descendants of immature macrophages and are thought to act as macrophages in disease and injury states [85].…”

Early treatment with Resolvin E1 facilitates myocardial recovery from ischaemia in mice

“…The pathogenesis of various inflammatory diseases, such as atherosclerosis (Brown et al, ), mammary cancer (Movahedi et al, ), brain ischaemia (Garcia‐Bonilla et al, ; Miro‐Mur et al, ), liver injury and fibrosis (Tacke and Zimmermann, ) and skeletal muscle repair after acute damage (Kharraz et al, ), are frequently associated with spatiotemporal dysregulation of Ly6C hi and Ly6C low Mos/Mps. It has been reported that treatment with bone morphogenetic protein‐7 mitigates atherosclerosis by enhancing Mo/Mp differentiation toward Ly6C low cells in ApoE −/− mice (Singla et al, ). Thus, targeting certain Mo/Mp populations may represent a useful therapeutic strategy for inflammatory diseases.…”

Primary human monocytes differentiate into M2 macrophages and involve Notch-1 pathway

“…These pro-inflammatory cytokines include IL-6, MCP-1, and TNF-α (Kleemann et al 2008;Outtz et al 2010;Singla et al 2014). Conversely, M2 macrophages are anti-inflammatory, and aid in the repair of damaged tissue, making them a potential candidate for therapeutic options (Rocher et al 2012;Singla et al 2016). Secreted from M2 macrophages are the anti-inflammatory cytokines IL-10 and IL-1RA, and show an increase in the expression of Arginase-1 enzyme important in reducing harmful nitric oxide production (Kleemann et al 2008;Outtz et al 2010;Singla et al 2014).…”