The dominant cells in most chronic inflammatory reactions are macrophages, which contribute to the reaction by secreting cytokines and growth factors that act on various cells, by destroying foreign invaders and tissues, and by activating other cells, notably T lymphocytes. Macrophages are professional phagocytes that act as filters for particulate matter, microbes, and senescent cells. They also function as effector cells that eliminate microbes in cellular and humoral immune responses (Chapter 5). But they serve many other roles in inflammation and repair. Here we review the basic biology of macrophages, including their development and functional responses.
Macrophages are tissue cells derived from hematopoietic stem cells in the bone marrow and from progenitors in the embryonic yolk sac and fetal liver during early development (
Fig. 3.18 ). Circulating cells of this lineage are known as monocytes. Macrophages are normally diffusely scattered in most connective tissues. In addition, they are found in specific locations in organs such as the liver (where they are called Kupffer cells), spleen and lymph nodes (sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages). Together these cells comprise the mononuclear phagocyte system, also known by the older (and inaccurate) name of reticuloendothelial system.
In inflammatory reactions, progenitors in the bone marrow give rise to monocytes, which enter the blood, migrate into various tissues, and differentiate into macrophages. Entry of blood monocytes into tissues is governed by the same factors that are involved in neutrophil emigration, such as adhesion molecules and chemokines. The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years. Thus, macrophages often become the dominant cell population in inflammatory reactions within 48 hours of onset. The macrophages that reside in tissues in the steady state (in the absence of tissue injury or inflammation), such as microglia, Kupffer cells, and alveolar macrophages, arise from the yolk sac or fetal liver very early in embryogenesis, populate the tissues, stay for long periods, and are replenished mainly by the proliferation of resident cells.
There are two major pathways of macrophage activation, called classical andalternative (
Fig. 3.19 ). Which of these two pathways is taken by a given macrophage depends on the nature of the activating signals.
• Classical macrophage activation may be induced by microbial products such as endotoxin, which engage TLRs and other sensors, and by T cell–derived signals,
Activated macrophages in inflammation Macrophages in skin, intestinal tract
Resident tissue macrophages Yolk (Kupffer cells, alveolar macrophages, sac microglia, etc.)
Progenitor in yolk sac, fetal liver
Fig. 3.18 Maturation of mononuclear phagocytes. (A) During inflammatory reactions, the majority of tissue macrophages are derived from hematopoietic precursors. Some long-lived resident tissue macrophages are derived from embryonic precursors that populate the tissues early in development. (B) The morphology of a monocyte and activated macrophage.
TLR-ligands,
ROS, NO, IL-10, lysosomal TGF-° enzymes
IL-1, TNF, IL-12, IL-6, chemokines
Anti-inflammatory effects, wound repair, fibrosis
Fig. 3.19 Classical and alternative macrophage activation. Different stimuli activate monocytes/macrophages to develop into functionally distinct populations. Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-γ. They phagocytose and destroy microbes and dead tissues and can potentiate inflammatory reactions. Alternatively activated macrophages are induced by other cytokines and are important in tissue repair and the resolution of inflammation.