Regulation of M1/M2 macrophage polarization by Sutherlandia frutescens via NFkB and MAPK signaling pathways

Sutherlandia frutescens is a medicinal plant, indigenous to South Africa, used to treat a number of conditions, including Type 2 Diabetes (T2D) and immune disorders. It is thought to have the capacity to regulate macrophage differentiation, thus impacting upon metabolic immune diseases and indicating a potential for ethnopharmaceutical use. In this paper we report the molecular action of S. fiutescens with regard to in vitro macrophage differentiation and potential functions in vivo involving inflammation and wound healing. The responses of cells of the RAW 264.7 murine macrophage cell line (a model for macrophage function) to hot aqueous or 100% ethanol extracts of S. frutescens prepared from a single plant source previously shown to target T2D were compared to determine the relative efficacy and action of each extract. Activation of the proinflammatory M1 phenotype and the anti-inflammatory M2 phenotype was investigated using the CD markers CD86 (M1) and CD206 (M2). Both S. frutescens extracts down-regulated CD86 expression, and the ethanolic extract up-regulated CD206, indicating stimulation of the M2 phenotype over the M1 phenotype. M1 macrophage pro-inflammatory responses in vitro, including nitric oxide and reactive oxygen species production and cyclo-oxygenase-2 (COX-2) expression were inhibited by both extracts.This is the first report of down regulation by S. frutescens of COX-2, a major pro-inflammatory mediator. Patterns of cytokine production determined by ELISA assays, showed down-regulation of the M1 pro-inflammatory cytokine profile, whilst the M2 cytokine profile remained unchanged. Reduced production of inflammatory mediators was associated with decreased activity of the mitogen activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF kappa B) signalling pathways. This novel finding in an in vitro model of macrophage responses to S. frutescens leads to the hypothesis that several medicinal properties of S. frutescens extracts are mediated by regulation of MAPK and NF kappa B cell signaling pathways leading to a reduction in MI macrophage activity and redirection towards M2 anti-inflammatory functions, thus promoting tissue remodeling and immune regulation. (C) 2018 SAAB. Published by Elsevier B.V. All rights reserved.