Macrophage biology in development, homeostasis and disease

Abstract

Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

Figure 1. Macrophages in Development, Homeostasis and Disease

Macrophages play many developmental roles shaping the architecture of tissues ranging from the brain to bone to the mammary gland. Once development is over macrophages modulate homeostasis and normal physiology through regulating diverse activities including metabolism and neural connectivity and by detecting damage. These trophic and regulatory roles however, are often subverted by continuous insult and macrophages contribute to many diseases that are often associated with aging.

Figure 2. Macrophage Lineages Re-Defined in Mice

The mononuclear phagocytic system in adults derives from at least three sources. The first is the yolk sac (YS) that results in progenitors that populate all tissues and their progeny persist throughout life as F4/80 bright resident macrophages. These lineages are largely regulated by CSF1R. The second from the fetal liver is less well defined but seems to contribute to adult LCs perhaps through a progenitor derived from the YS. The third lineage derives from the bone marrow (BM) to give circulating monocytes and their progeny F4/80^low macrophages and DCs. In this case the Ly6c+ monocytes give rise to classical DCs under the regulation of FLT3 and these are continuously replenished. Other macrophages that are F4/80 low also emanate from Ly6c⁺ monocytes and in some cases such as kidney and lung, co-exist with those derived from YS to give chimeric organs. The exact role of the patrolling Ly6cmacrophages remains unclear, as is the contribution of fetal liver to adult tissue macrophages.

Figure 3. Activated and alternatively activated macrophages differentially regulate insulin sensitivity in obesity

In lean healthy animals, adipose tissue macrophages comprise 10–15% of stromal cells and express markers that link them with alternatively-activated macrophages, which are critical for maintaining insulin sensitivity in adipocytes, in part via the production of IL-10. Type-2 cytokines such as IL4 and IL13 derived from a variety of cellular sources, including eosinophils, appear to be important for maintaining the AAM phenotype in lean tissues. In contrast, during obesity Ly6C^hi monocytes are recruited, which increases macrophage content to 45–60%. These macrophages, in contrast to normal resident macrophages, express an inflammatory phenotype, characterized by the production of TNFα, IL6 and IL1β These inflammatory macrophages decrease insulin sensitivity while facilitating the storage of excess nutrients. The enlarging white adipose tissues in turn release chemokines, such as CCL2, CcCL5, and CCL8, to recruit additional Ly6C^hi inflammatory monocytes that further exacerbate the process. This mechanism is also enhanced during bacterial and viral infections so essential nutrients are diverted to lymphocytes, which must utilize glycolysis to enhance their activation at times of stress.

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.