Macrophage Activation

Siamon Gordon, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

The modern concept of the 'angry macrophage (M0)', the immunologically activated cell generated during infection of the host by intracellular pathogens such as bacille Calmette-Guèrin (BCG) and Listeria, dated from the work of Mackaness and his colleagues at the Trudeau Institute in the 1960s. Whilst T lymphocytes become activated by antigen-specific pathways, their production of M0-activating lym-phokines, later shown by various workers to be mainly interferon y (IFNy), results in enhanced antimicrobial activity directed nonspecifically against a range of microorganisms. This interaction between T lymphocytes and Ma lies at the heart of cellular immunity and delayed-type hypersensitivity. Subsequent studies have shown that a specialized antigen presenting cell related to M0 (the dendritic cell), plays a key role in the activation of T lymphocytes by foreign antigens and that T helper lymphocyte subset 1 (Tnl) responses are mainly responsible for M0 activation, whereas TH2 responses modulate Th1 and M0 activation. The major antimicrobial products of the activated M0 include reactive oxygen and nitrogen metabolites, and the range of targets can be extended to viruses including human immunodeficiency virus (HIV), and possibly tumor cells. The importance of M0 activation in host defence and pathogenesis of tissue injury has been underlined by experimental 'knock out' of key genes in the above pathway, and in genetic and acquired diseases in humans.

The M0 also plays a central role in innate immunity, in the absence of T cell activation, and interacts with specific antibody to enhance humoral defense mechanisms. The immunobiology of M0 can be compared with that of neutrophils and other myeloid cells, as well as natural killer (NK) cells and cytotoxic T lymphocytes. Some of the differences and similarities of M0 responses compared with those of other cells will be brought out below.

The definition of M0 activation given above is a relatively strict one and there are circumstances where it may break down. For example, microbial particulates and products, especially lipopolysaccha-

rides (LPS), have complex direct and indirect effects on M0 defense functions. Whilst well able to interact with and amplify IFNy-induced responses of M0, these agents also 'activate' a range of antimicrobial systems in the absence of IFNy. Phagocytic stimulation via plasma membrane receptors involving specific antibody (FcR), other opsonins (e.g. complement) and opsonin-independent recognition of particulates profoundly alter the pattern of M0 gene expression, with overlap and differences from the IFNy-induced modulation associated with immune, T cell-dependent activation. There is marked heterogeneity of the M0 phenotvpe within the host reflecting intrinsic changes in their differentiation and extrinsic modulation by cytokines and other factors in their microenvironment. The wide repertoire of plasma membrane receptors and biosynthetic responses, combined with extensive endocytic activity and vacuolar specialization, involve a complex set of M0-specific and nonspecific gene products and signaling pathways which are still far from unraveled. Some simplifying concepts are now, however, well established and will be summarized here.

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