Macrophages are key regulators of the innate immune system, where they can detect, phagocytose and destroy foreign
antigens.91 Apart from tissue destruction, it is now known that macrophages also play an important role in tissue homeostasis, cellular replacement and repair through the clearance of apoptotic cells and cellular debris. They also produce mediators that downregulate inflammation Trichostatin A order and promote remodelling and regeneration. The immunomodulatory effects of MSC on T lymphocytes, B lymphocytes, natural killer cells and dendritic cells have been extensively investigated (for review34,92). However, less is known about their ability to modulate macrophage phenotype and function. The activation state that governs macrophage function is dependent see more on the inflammatory stimuli received from the tissue microenvironment. As the process of repair shifts from the initial inflammatory phase to that of remodelling, macrophages subsequently exhibit varying polarization states and exert a diverse range of functional activities.93 Although a variety of classification methods have been proposed, macrophages are typically
believed to exist in one of two opposing polarization states, that is, the M1 ‘classically activated’ subset or M2 ‘alternatively activated’ subset.94 M1 polarization is achieved through a combination of events. The first ‘priming’ step involves exposure of the
macrophage to IFN-γ.91 The second signal requires the exposure to either a microbial product, such as lipopolysaccharide (LPS), or proinflammatory cytokines, such as TNF, to the macrophage, resulting in M1 activation.91 M1 macrophages are characterized by their enhanced ability to phagocytose and present antigen through the upregulation of MHC class II and the co-stimulatory molecules CD80 and CD86.95 They secrete numerous pro-inflammatory cytokines, particularly IL-12 and IL-23, which induce the downstream production of the toxic intermediates nitric oxide Selleckchem Sorafenib and reactive oxygen species (ROS) as well as promoting the killing and degradation of intracellular microorganisms.91,96 It was previously believed that Th2 derived cytokines had a deactivating effect on macrophages.97 However, in 1992, Stein et al.98 demonstrated that macrophages exposed to IL-4 took on an ‘alternative’ phenotype, characterized by reduced secretion of proinflammatory cytokines. It has since been reported that exposure to IL-13, IL-10, TGF-β, glucocorticoids and immune complexes in combination with IL-1β or LPS can also induce an M2 alternative polarization state.94 In contrast to their classically activated counterpart, M2 macrophages are involved in dampening the inflammatory response, while exhibiting enhanced scavenging abilities that promote tissue remodelling and repair.