Information processing during phagocytosis

Abstract

Phagocytosis - the process by which macrophages, dendritic cells and other myeloid phagocytes internalize diverse particulate targets - is a key mechanism of innate immunity. The molecular and cellular events that underlie the binding of targets to a phagocyte and their engulfment into phagosomes have been extensively studied. More recent data suggest that the process of phagocytosis itself provides information to myeloid phagocytes about the nature of the targets they are engulfing and that this helps to tailor inflammatory responses. In this Review, we discuss how such information is acquired during phagocytosis and how it is processed to coordinate an immune response.

Figure 1. Information processing at different stages of phagocytosis

As phagocytosis proceeds from the initial binding of a target to actin-dependent internalization and ultimately to degradation of the target in the phagolysosome, myeloid cells acquire information about the target by a variety of mechanisms. At the surface, receptors sample the chemical constituents of the particle and membrane dynamics facilitate assessment of its physical properties. Additional information is gathered as the phagosome pinches off from the plasma membrane and as it matures through interactions with other intracellular compartments. Finally, degradation of the target exposes ligands that weren’t previously accessible, and releases ligands into the cytosol for detection by intracellular receptors. The information gathered by all of these processes is integrated to shape the ensuing immune response.

Figure 2. Phagocytic synapse formation permits Dectin-1 to distinguish between soluble and particulate β-glucans

Dectin-1 engages both particulate β-glucans and soluble β-glucan polymers, but only particulate β-glucans activate phagocytosis and inflammatory responses. CD45 and CD148 phosphatases regulate signal transduction by the Dectin-1 hemITAM, and must be isolated from the clustered receptors by the formation of a synapse in order to permit productive Dectin-1 signaling. Soluble β-glucans bind with high affinity to Dectin-1 but do not form synapses and therefore fail to trigger Dectin-1-mediated responses.

Figure 3. TLR4 signal transduction from the cell surface, endosomes and phagosomes

TLR4 signals via the MyD88 adaptor at the cell surface and via TRIF from intracellular compartments. Recruitment of TLR4 for TRIF-mediated signaling is differentially regulated when cells undergo endocytosis of soluble LPS and phagocytosis of LPS-containing bacteria.

Figure 4. Macrophages can differentiate between live and dead E. coli by the detection of ‘vita-PAMPs’

During phagocytosis, macrophages assess whether E. coli are alive or dead. While some responses are triggered by engagement of both live and dead bacteria at the cell surface (e.g. IL-6 production), other responses are only initiated upon internalization of live bacteria (e.g. inflammasome activation, which is required for processing of IL-1β). When live bacteria are degraded they release RNA, which is thought to leak out of the phagolysosome and be detected by cytosolic receptors. However, RNA is rapidly degraded when bacteria die, so no RNA is released when dead bacteria are phagocytosed.