Trigger

Microorganism a Phagocytosis

Lps MHC class II'

Monotylo PRIMED ACTIVATED KILL

resident elicited

Figure 2 Two-stage activation of macrophages. Different stages of resident and recruited m0 require action of ifn7 to become primed. Local stimuli, often microbial products, trigger surface changes and production of cytokines such as TNFa and reactive oxygen metabolites. Neutral proteinases such as PA can be induced by ifn7 and their release triggered by phagocytosis, but are also induced by nonactivating cytokines, for example CSF-1.

requirement for priming by specific cytokines allows subtle control of appropriate gene expression in the Mo, which is biosynthetically more adaptable than neutrophils, for example, which store preformed products or can activate microbicidal pathways directly. TH1 and TH2 lymphocytes, NK, dendritic and other local cells, as well as M0 themselves, play a major role in regulation of Me priming via cytokines (IL-12, IL-18, IFNy, IL-4/13, IL-10, IL-6, transforming growth factor (3 (TGF(3), IFNa/p) and other mediators (glucocorticoids, prostaglandins); cell surface molecules (e.g. MHC class II/CD4, adhesion molecules such as integrins and ICAMS, and immune accessory molecules such as B-l/B-2) also control hematopoietic and other cellular interactions (Figure 3).

Recent studies have shown that Me priming and activation cover a phenotypic spectrum of cytokine actions on M0 (Figure 3 and Table 1) in which it is possible to distinguish not only the polar opposites of activation (IFNy) and deactivation (IL-10), but also an intermediate phenotype, termed alternate activation (IL-4, IL-13). This spectrum of M0 properties is summarized in Table 1 and indicates considerable diversification of function, depending on their roles in cellular versus humoral immunity, inflammation and repair. It is likely that these described phenotypes, which are mainly based on in vitro studies, with isolated cells and individual cytokines, coexist in vivo, and that the net outcome of M0 activities within tissues will depend on their reciprocal interactions.

Plasma membrane triggers vary widely in their effects

M0 express a wide range of surface receptors for opsonins and direct microbial recognition as well as for migration, adhesion, cytokine responses and cellular interactions (Table 2). These vary considerably in their ability to trigger Ma biosynthetic and secretory responses; e.g. receptor for Fc fragment of immunoglobulin G (FcR) induces a respiratory burst and arachidonate release, whereas CR3 does not, in various experimental models. Other receptors, such as scavenger receptor type A(SR-A), may dowregu-late M0 responses to LPS, either by competition among different receptors for LPS (SR-A versus CD14, the receptor for LPS-binding protein), or by postmembrane interactions that are not yet clear. Another question that is not fully resolved is to what extent surface ligation and clustering of receptors is sufficient to trigger M0 secretion, compared with ingestion of phagocytic targets. Differential expression by activated Ma of plasma membrane receptor levels, e.g. reduced mannose receptor, may also not correlate with their ability to mediate secretory responses. Finally, there is still little understanding of receptor turnover and changes in intracellular compartments (endosomal, lysosomal) that accompany immune activation. Receptor-mediated endocytosis is strikingly influenced by different cytokines, and receptor molecules can be induced to undergo proteolytic cleavage and shedding as well as degradation by triggering agents.

Trigger

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