Box 1 | Differentiation, distribution and activation of macrophages in vivo
From the following article:
Alternative activation of macrophages
Siamon Gordon
Nature Reviews Immunology 3, 23-35 (January 2003)
doi:10.1038/nri978
The growth and differentiation of macrophages depends on lineage-determining cytokines, such as macrophage colony-stimulating factor (M-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF), and interactions with stroma in haematopoietic organs. Interleukin-3 (IL-3), KIT, tumour-necrosis factor (TNF)-family proteins and TNF-receptor-related molecules contribute to macrophage determination, as do key transcription factors such as PU.1 and other ETS-family members. A common progenitor gives rise to tissue macrophages, myeloid dendritic cells (DCs) and osteoclasts, which are distinct, irreversibly differentiated sublineages. Once distributed through the blood stream, monocytes constitutively enter all tissue compartments of the body. Resident macrophage populations in different organs — such as Kupffer cells (liver), alveolar macrophages (lung) and microglia (central nervous system, CNS) — adapt to their local microenvironment. The signals that are responsible for tissue-specific phenotypes of macrophages include surface and secretory products of neighbouring cells, and extracellular matrix. Adhesion molecules control cell migration from the blood, and through endothelia (as well as trapping endothelium-resident macrophages), the interstitium and epithelia. These include integrins (
1, 2 and others), immunoglobulin-superfamily molecules (such as CD31), selectins and epidermal growth factor seven-transmembrane spanning (EGF-TM7)-type receptors related to the F4/80 (EMR1) antigen107. Cytokines such as transforming growth factor-, chemokines and growth factors, often bound to local proteoglycans, influence the expression of a range of macrophage genes. Tissue-resident macrophages cease to proliferate, but they have active messenger RNA and protein synthesis. Although macrophages might die in situ, they can be induced to migrate to draining lymph nodes, where they are filtered from the afferent lymph. They do not enter efferent lymphatics or the thoracic duct, unlike DCs. It is possible that monocyte-derived tissue macrophages can re-enter the blood stream and differentiate into DCs, depending on local stimuli such as phagocytosis, leukotrienes and a multidrug-transporter ATPase108.
Tissue-resident macrophages undergo local activation in response to various inflammatory and immune stimuli; the enhanced recruitment of monocytes and precursors from bone-marrow pools results in the accumulation of tissue macrophages that have enhanced turnover and an altered phenotype. These macrophages are classified as being 'elicited', as in the antigen-non-specific response to a foreign body or sterile inflammatory agent, or as being 'classically activated' or 'alternatively activated' by an antigen-specific immune response. It is difficult to distinguish originally resident macrophages from more recently recruited, elicited or activated macrophages, because cells adapt to a particular microenvironment.
