Receptors That Inhibit Macrophage Activation: Mechanisms and Signals of Regulation and Tolerance

Abstract

A variety of receptors perform the function of attenuating or inhibiting activation of cells in which they are expressed. Examples of these kinds of receptors include TIM-3 and PD-1, among others that have been widely studied in cells of lymphoid origin and, though to a lesser degree, in other cell lines. Today, several studies describe the function of these molecules as part of the diverse mechanisms of immune tolerance that exist in the immune system. This review analyzes the function of some of these proteins in monocytes and macrophages and as well as their participation as inhibitory molecules or elements of immunological tolerance that also act in innate defense mechanisms. We chose the receptors TIM-3, PD-1, CD32b, and CD200R because these molecules have distinct functional characteristics that provide examples of the different regulating mechanisms in monocytes and macrophages.

Figure 1

Schematic representation of the structures of inhibitory receptors. All receptors belong to the superfamily of immunoglobulins. They have a single transmembrane portion and an intracellular tail, through which they associate with proteins or effector enzymes. The immunoglobulin domains are represented as blue ovals for receptors and red ovals for ligands.

Figure 2

Inhibition mechanism of IL-12 production through interaction of TIM-3 and Gal-9. Graphic representation of the TLR4-signaling pathway (black arrows) when activated by LPS (to simplify, not all proteins involved are shown), which induces phosphorylation of diverse nuclear factors, such as NF-κB (p50-p65), AP-1, and STAT1. These nuclear factors induce production of proinflammatory molecules like IL-12. When TIM-3 interacts with Gal-9, phosphorylation of the intracellular portion of TIM-3 is induced and activates the regulatory pathway mediated by this protein. While we do not yet know the precise inhibition mechanism in macrophages, studies have identified a decrease in STAT1 phosphorylation and an increase in STAT3 phosphorylation (red arrows). The result of this change is reduced IL-12 production and increased IL-23 production.

Figure 3

Inhibition mechanism of the FcγR receptor (CD32). (a) When CD32b recognizes the Fc fraction of IgG, the phosphatase SHP or SHIP is recruited into the ITIM domains of the intracellular portion of the receptor. Those enzymes inhibit phosphorylation of the ITAM domains or eliminate phosphorylation of the ITAM domains contained in CD32a. This mechanism inhibits the activation of macrophages and the phagocytosis of opsonized pathogens and other elements that are susceptible to recognition by IgG-class antibodies. (b) When the association of CD32a is greater than the frequency of CD32b receptors, phosphatase recruitment is not fostered and, therefore, no inhibition of the activation signals mediated by phosphorylation of the ITAM domains in the intracellular portion of CD32b is produced. As a result, the corresponding internalization mechanisms are activated.

Figure 4

CD200R-induced signaling pathway. Interaction of CD200R with its ligand induces phosphorylation of the tyrosine residues (red squares) present in the intracellular portion of the receptor mediated by kinases of the Src family. This mechanism propitiates recruitment of Dok2 through its binding domain to tyrosine (PTB). Dok2 binds to the phosphorylated tyrosines, and it recruits the activator protein of Ras-GTPase (RasGAP), which inhibits Ras and downstream ERK activation. ERK is a MAP kinase which is involved in macrophages activation by IFN-γ. JAK/STAT-1 signaling pathway is required for cell activation, and STAT-1 is phosphorylated by JAK proteins and ERK-1/2 in turn to allow the gene expression for cell differentiation, growth and metabolism, so then, if CD200R binds to its ligand CD200 it allows the inhibition of cell activation [74, 95].