Various microenvironmental cues determine selleck chem Ruxolitinib monocyte fate which can lead to differentiation into macrophage and dendritic cells . However monocytes are not simply macrophage and dendritic cell precursors but are also immune effector cells . Under inflammatory conditions, circulating monocytes can be recruited to the site of infection or injury, and once there, differentiate. However under steady state conditions, local proliferation maintains resident macrophages Inhibitors,research,lifescience,medical in sites such as the lungs and liver. Macrophages (Ms) are central players in the development, progression, and resolution of inflammation . They are polarized following activation into classic (or M1) and alternative (or M2) macrophages [13–15]. M1 macrophages
are activated in response to microbial products such as lipopolysaccharide (LPS) or cytokines like interferon-γ (IFN-γ) and tumour necrosis factor α (TNFα) and are characterized by a strong
propensity to present antigen. In a polarized response, M1 cells Inhibitors,research,lifescience,medical are thought to kill intracellular microorganisms and produce abundant proinflammatory cytokines such as TNF-α, interleukin (IL)-12, IL-23, and proinflammatory mediators like nitric oxide (NO) and reactive oxygen intermediates (ROI). On the other hand, M2 macrophages are promoted by various signals such as IL-4, IL-13, Inhibitors,research,lifescience,medical glucocorticoids, IL-10, immune complexes and some pathogen-associated molecular patterns (PAMPs) that elicit different M2 forms (M2a, b and c). They function in inflammation resolution and tissue remodelling. Pathogen Recognition Receptors (PRRs) have evolved to recognise conserved molecular-associated molecular patterns (PAMPS) from pathogens, such as lipopolysaccharide or bacterial Inhibitors,research,lifescience,medical DNA motifs. The Toll-like receptors (TLRs) are one such family whose ligands have generated much excitement over the last decade as immunostimulatory adjuvants Inhibitors,research,lifescience,medical in vaccine selleck chemical Trichostatin A development . Engagement of TLRs by their cognate
ligands will activate antigen presenting cells, stimulate cytokine secretion that regulates the adaptive immune response, and promote up regulation of costimulatory molecules in order to improve antigen Dacomitinib presentation to T cells. Thus incorporation of TLR ligands or immunomodulatory moieties into liposomes has been a strategy for improving efficacy of both vaccine development and drug targeting . For example, as TLR ligands have been shown to activate macrophages and dendritic cells and enhance antigen-specific T cell responses, then enhanced uptake of PAMP-coated liposomes into these cells would be expected. However, whilst TLR ligands and PAMPs in general can increase liposome uptake, their ability to stimulate and activate macrophages and enhance antigen-specific T cell activation and immune reactivity would suggest that their potential inflammatory properties may be an issue for general use in targeting strategies . In this respect other target receptors such as the scavenger receptors and mannose receptors may prove more appropriate.