SMAD-PI3K-Akt-mTOR Pathway Mediates BMP-7 Polarization of Monocytes into M2 Macrophages

Abstract

Previously we demonstrated that bone morphogenetic protein-7 (BMP-7) treatment polarizes monocytes into M2 macrophages and increases the expression of anti-inflammatory cytokines. Despite these findings, the mechanisms for the observed BMP-7 induced monocyte polarization into M2 macrophages are completely unknown. In this study, we demonstrate the mechanisms involved in the polarization of monocytes into M2 macrophages. Apoptotic conditioned media (ACM) was generated to mimic the stressed conditions, inducing monocyte polarization. Monocytes were treated with ACM along with BMP-7 and/or its inhibitor, follistatin, for 48 hours. Furthermore, an inhibitor of the PI3K pathway, LY-294002, was also studied. Our data show that BMP-7 induces polarization of monocytes into M2 macrophages while significantly increasing the expression of anti-inflammatory markers, arginase-1 and IL-10, and significantly (p<0.05) decreasing the expression of pro-inflammatory markers iNOS, IL-6, TNF-α and MCP-1; (p<0.05). Moreover, addition of the PI3K inhibitor, LY-294002, significantly (p<0.05) decreases upregulation of IL-10 and arginase-1, suggesting involvement of the PI3K pathway in M2 macrophage polarization. Next, following BMP-7 treatment, a significant (p<0.05) increase in p-SMAD1/5/8 and p-PI3K expression resulting in downstream activation of p-Akt and p-mTOR was observed. Furthermore, expression of p-PTEN, an inhibitor of the PI3K pathway, was significantly (p<0.05) increased in the ACM group. However, BMP-7 treatment inhibited its expression, suggesting involvement of the PI3K-Akt-mTOR pathway. In conclusion, we demonstrate that BMP-7 polarizes monocytes into M2 macrophages and enhances anti-inflammatory cytokine expression which is mediated by the activated SMAD-PI3K-Akt-mTOR pathway.

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

“…In fact, bone morphogenetic protein-7 (BMP-7) mediates monocyte polarization into M2 macrophages through the activation of the PI3K-AKT-mTOR pathway [24] and RAPA, by blocking mTOR, and unbalances the polarization of human macrophages towards the M1 status [25]. …”

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

“…Of distinct interest are macrophages, as they are key responders in inflammatory processes (Fung et al 2007;Moore et al 2013;Outtz et al 2010). When an injury occurs, macrophages migrate to the area and differentiate into two polarized subclasses, M1 and M2 macrophages (Kigerl et al 2009;Rocher and Singla 2013). Understanding the mechanisms by which these macrophages polarize and their specific roles in disease states are key to identifying novel treatments for ATH.…”

mTOR mediates the cross-talk of macrophage polarization and autophagy in atherosclerosis

“…A specific inhibitor of mTOR pathway rapamycin which has become a clinical trial drug can selectively promote moderate autophagy of macrophage and keep atherosclerotic plaque stable [14]. In addition, in bone marrow derived macrophages, activation of the PI3K-mTOR pathway resulted in increased polarization of M2 macrophages and inhibition of either PI3K or mTOR resulted in M1 macrophage polarization demonstrating the importance of this pathway in the polarization of macrophages [15]. Therefore, we can deduce that selective inhibition of the mTOR signal transduction pathway can reduce M1 phenotype macrophages and stabilize the vulnerable atherosclerotic plaques by promoting macrophage autophagy.…”