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Review
. 2017 Nov 24;429(23):3561-3576.
doi: 10.1016/j.jmb.2017.08.012. Epub 2017 Aug 25.

LC3-Associated Phagocytosis and Inflammation

Bradlee L Heckmann  1 , Emilio Boada-Romero  1 , Larissa D Cunha  1 , Joelle Magne  1 , Douglas R Green  2
Affiliations
Review

LC3-Associated Phagocytosis and Inflammation

Bradlee L Heckmann et al. J Mol Biol. .

Abstract

LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B-light chain 3) is conjugated to phagosome membranes using a portion of the canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an "immunologically silent" clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages.

Keywords: LC3-associated phagocytosis; autophagy; efferocytosis; immune regulation; metabolism.

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Figures

Figure 1
Figure 1. Overview of LC3-associated phagocytosis
Molecules on the surface of cargo are detected by receptors located in the plasma membrane of the phagocyte (such as TIM4 for PtdSer, FcR for Ig-opsonized particles, or TLRs and other PRR for PAMPs). The cytoskeleton rearranges and curves the plasma membrane to produce the phagosome cup. When the plasma membrane closes around the extracellular cargo (not depicted), the phagosome cup is sealed into an early phagosome produced in the cytosol of the phagocyte. Then, the early phagosome matures to become a late phagosome in a process involving membrane modifications and ROS generation. Lysosomes contain hydrolases and by fusion to the late phagosome, these are transferred to the phagosome lumen and the enclosed phagosome cargo is degraded producing nutrients and second messengers. The three panels in the inset depict the molecular machinery in the pathway: the PI3KC3 complex (upper panel) produces PI3P, the NOX2 complex (middle panel) is responsible of the oxidative burst. The two UB-like conjugation systems (lower panel) lipidate LC3 proteins on the phagosome membranes. See text for further details.
Figure 2
Figure 2. Physiological outcomes of LC3-associated phagocytosis in autoimmunity
Macrophages that are sufficient in the LAP pathway are able to efficiently clear apoptotic cells and pathogens. There is a rapid lysosomal fusion and degradation of target cargo that occurs. This timing results in the production of anti-inflammatory cytokines and dampening of the immune response, leading to a decreased risk of autoimmunity. In contrast, macrophages deficient in LAP have an abrogation in the clearance of apoptotic cells. Moreover, the reduced rate of phagosome-lysosomal fusion results in the establishment of a more pro-inflammatory cytokine profile. Additionally, in the absence of LAP there is likely an increased amount of autoantigen presentation. Taken together, these factors greatly increase the risk for developing autoimmunity, as is evident in the establishment of SLE in LAP-deficient mice.
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