importantly the cytokine IFN-γ, in immune responses. Classically activated (also called M1) macrophages produce NO and ROS and upregulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against microbes and in many inflammatory reactions.
• Alternative macrophage activation is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells. These macrophages are not actively microbicidal; instead, the principal function of alternatively activated (M2) macrophages is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis.
It seems plausible that in response to most injurious stimuli, the first activation pathway is the classical one, designed to destroy the offending agents, and this is followed by alternative activation, which initiates tissue repair. However, such a precise sequence is not well documented in most inflammatory reactions. In addition, although the concept of M1 and M2 macrophages provides a useful framework for understanding macrophage heterogeneity, numerous other subpopulations have been described and the M1 and M2 subsets are not fixed.
The products of activated macrophages eliminate injurious agents such as microbes and initiate the process of repair, but are also responsible for much of the tissue injury in chronic inflammation. Several functions of macrophages are central to the development and persistence of chronic inflammation and the accompanying tissue injury.
Macrophages secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines, and others) and eicosanoids. Thus, macrophages are central to the initiation and propagation of inflammatory reactions.
Macrophages display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that is essential for defense against many microbes by cell-mediated immune responses. These interactions are described further in the discussion of the role of lymphocytes in chronic inflammation, later in this chapter, and in more detail in Chapter 5 where cell-mediated immunity is considered.
Their impressive arsenal of mediators makes macrophages powerful allies in the body’s defense against unwanted invaders, but the same weaponry can also induce considerable tissue destruction when macrophages are inappropriately or excessively activated. It is because of these activities of macrophages that tissue destruction is one of the hallmarks of chronic inflammation.
In some instances if the irritant is eliminated, macrophages eventually disappear (either dying off or making their way via lymphatics into lymph nodes). In others, macrophage accumulation persists, as a result of continuous recruitment from the circulation and local proliferation at the site of inflammation.
Role of Lymphocytes
Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation. Although the major function of these lymphocytes is as the mediators of adaptive immunity, which provides defense against infectious pathogens (Chapter 5), these cells are often present in chronic inflammation and, when they are activated, the inflammation tends to be persistent and severe. Some of the strongest chronic inflammatory reactions, such as granulomatous inflammation, described later, are dependent on lymphocyte responses. Lymphocytes may be the dominant population in the chronic inflammation seen in autoimmune and other hypersensitivity diseases.
By virtue of their ability to secrete cytokines, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reaction. These T cells greatly amplify the early inflammatory reaction that is induced by recognition of microbes and dead cells as part of the innate immune response. There are three subsets of CD4+ T cells that secrete different cytokines and elicit different types of inflammation.
TH1 cells produce the cytokine IFN-γ, which activates macrophages by the classical pathway.