Figure 4. Macrophages exhibiting unique activation profiles regulate disease progression and resolution.

Macrophages are highly plastic cells that adopt a variety of activation states in response to stimuli found in the local milieu. During pathogen invasion or following tissue injury, local tissue macrophages often adopt an activated or “inflammatory phenotype”. These cells are commonly called “classically activated” macrophages (CAM), because they were the first activated macrophage population to receive a formal definition. These macrophages are activated by IFN-γ and/or following Tolllike receptor engagement, leading to the activation of the NF-kβ and Stat1 signaling pathways, which in turn increases production of reactive oxygen and nitrogen species and pro-inflammatory cytokines like TNF-α, IL-1, and IL-6 that enhance antimicrobial and anti-tumor immunity, but may also contribute to the development of insulin resistance and diet-induced obesity. Epithelial derived alarmins and the type-2 cytokines IL4 and IL13, in contrast, result in an “alternative” state of macrophage activation that has been associated with wound healing, fibrosis, insulin sensitivity, and immunoregulatory functions. These wound healing, pro-angiogenic, and pro-fibrotic macrophages (PfMø) express TGF-β1, PDGF, VEGF, WNT ligands, and various matrix metalloproteinases that regulate myofibroblast activation and deposition of extracellular matrix components. Alternatively activated macrophages (AAMs) also express a variety of immunoregulatory proteins like arginase-1 (Arg1), Relm-alpha (Retnla), Pdl2, and Il10 that regulate the magnitude and duration of immune responses. Therefore, in contrast to CAMs that activate immune defenses, AAMs are typically involved in the suppression of immunity and re-establishment of homeostasis. Although type-2 cytokines are important inducers of suppressive or immunoregulatory macrophages, it is now clear that several additional mechanisms can also contribute to the activation of macrophages with immunoregulatory activity. Indeed, IL10-producing Tregs, Fc gamma receptor engagement, engulfment of apoptotic cells, and prostaglandins have also been shown to preferentially increase the numbers of regulatory macrophages (Mregs) that suppress inflammation and inhibit anti-microbial and anti-tumor defenses. The tumor microenvironment itself also promotes the recruitment and activation of immune inhibitory cells, including those of the mononuclear phagocytic series such as myeloid-derived suppressor cells (MDSCs), tumor-infiltrating macrophages (TIMs), tumor-associated macrophages (TAMs) and metastasis-associated macrophages (MAMs) that promote angiogenesis and tumor growth, while suppressing anti-tumor immunity.