Prix Fixe: Efferocytosis as a Four-Course Meal

Abstract

During development, stress, infection, or normal homeostasis, billions of cells die on a daily basis, and the responsibility of clearing these cellular corpses lies with the phagocytes of innate immune system. This process, termed efferocytosis , is critical for the prevention of inflammation and autoimmunity , as well as modulation of the adaptive immune response. Defective clearance of dead cells is characteristic of many human autoimmune or autoinflammatory disorders, such as systemic lupus erythematosus (SLE), atherosclerosis, and diabetes. The mechanisms that phagocytes employ to sense, engulf, and process dead cells for an appropriate immune response have been an area of great interest. However, insight into novel mechanisms of programmed cell death , such as necroptosis, has shed light on the fact that while the diner (or phagocyte) is important, the meal itself (the type of dead cell) can play a crucial role in shaping the pursuant immune response.

Fig. 1

The recruitment of phagocytes to sites of cell death and recognition and engulfment of apoptotic cells by phagocytes. a Apoptotic cells (or other dying cells) release “find-me” signals, such as ATP, UTP, S1P, LPC, or fractalkine, that act to recruit phagocytes to sites of cell death. Phagocytes sense these “find-me” signals via cognate receptors (P2Y2, S1PRs, G2A, and CXCR3, respectively). b Phagocytes employ a system of receptors and bridging molecules to recognize and engage apoptotic cells (or other dying cells) via “eat-me” signals exposed on apoptotic cell surfaces. The most common “eat-me” signal is phosphatidylserine (or PS), which engages the PS-specific receptors, TIM1, TIM3, TIM4, BAI1, stabilin-2, and RAGE, as well as the PS-specific bridging molecules MFG-E8, Gas6, and protein S. These bridging molecules engage other surface engulfment receptors (α_vβ₃ or TAM) to facilitate uptake. Other “eat-me” signals, such as calreticulin (CRT) and ICAM3, exist and mediate recognition and engulfment via the receptors LRP (via C1q) and CD14, respectively. c Once the engulfment receptors are engaged, actin polymerization and cytoskeletal rearrangement are initiated via activation of the Rac1 pathway. While some engulfment receptors utilize the ELMO1/DOCK180 complex (α_vβ₃, TAM, stabilin-2, LRP), the mechanism by which TIM4 activates the Rac1 pathway is unknown. Perturbations at any step of this process can result in inflammation and autoimmunity

Fig. 2

The processing and digestion of engulfed apoptotic cells utilizes LC3-associated phagocytosis and promotes an anti-inflammatory response. Upon engulfment of apoptotic cells (or other dying cells), components of the LC3-associated phagocytosis (LAP) pathway are recruitment to dead cell-containing phagosome (or LAPosome). The Class III PI3 K complex, composed of Beclin-1, VPS34, UVRAG, and Rubicon, is critical to the sustained and localized production of PI(3)P at the LAPosome. PI(3)P serves two roles—the recruitment of the downstream autophagic/LAP machinery (such as ATG5, ATG12, ATG16L, ATG7) and stabilization of the NOX2 complex for the production of ROS. Of note, Rubicon is also required for the stabilization of the NOX2 complex. Both ROS and PI(3)P are required for lipidation and translocation of LC3-II to the single membrane of the LAPosome, and LC3-II is required for fusion to the lysosome and maturation of LAPosome. The anti-inflammatory effects of efferocytosis are mediated by the activity of lipid and cholesterol sensors, such as ABCA1, LXR, PPARγ, PPARδ, and PGC-1β, leading to the production of anti-inflammatory mediators, IL-10 and TGFβ. Pro-inflammatory mediators, such as IL-12, are actively repressed. Perturbations in this process can result in inflammation and autoimmunity